Mayer was born into a Jewish family who fled to the United States during the Nazi invasion of Luxembourg in May 1940. He became a naturalized US citizen in 1944.

Mayer received his education at the City College of New York and Yale University. He has been professor at Wesleyan University (1952-1953), Brandeis University (1954-1958) and Harvard University (1958-1961). He has taught at Princeton University since 1961.

A self-proclaimed "left dissident Marxist", Mayer's major interests are in modernization theory and what he calls "The Thirty Years' Crisis" between 1914 and 1945. In Mayer's view, Europe was characterized in the 19th century by rapid modernization in the economic field by industrialization and retardation in the political field. Mayer has argued that he calls the "Thirty Years' Crisis" was caused by the problems of a dynamic new society produced by industrialization facing a rigid political order. In particular, Mayer feels that the aristocracy in all of the European countries held far too much power, and it was their efforts to keep power that led to World War I, the rise of fascism, World War II, and the Holocaust.

In a 1967 essay "The Primacy of Domestic Politics", Mayer made a Primat der Innenpolitik ("primacy of domestic politics") argument for the origins of World War I. Mayer rejected the traditional Primat der Außenpolitik ("primacy of foreign politics") argument of traditional diplomatic history under the grounds that it failed to take into account that in Mayer's opinion, all of the major European countries were in a "revolutionary situation" in 1914, and thus ignores what Mayer considers to the crucial impact that domestic politics had on foreign-policy making elites. In Mayer's opinion, in 1914, the United Kingdom of Great Britain and Ireland was on the verge of civil war and massive industrial unrest, Italy had been rocked by the Red Week of June 1914, the French Left and Right were waging a war to the death with each other, Germany was faced with ever-increasing political strife, Russia was facing a huge strike wave, and Austria-Hungary was confronted with rising ethnic and class tensions. Moreover, Mayer insists that liberalism and centrist ideologies in general were disintegrating in face of the challenge from the extreme right in the UK, France and Italy while being a non-existent force in Germany, Austria-Hungary and Russia. Mayer ended his essay by arguing that World War I should be best understood as a pre-emptive "counterrevolutionary" strike by ruling elites in Europe to preserve their power by distracting public attention onto foreign affairs.

In his 1967 book Politics and Diplomacy of Peacemaking: Containment and Counter-Revolution at Versailles, Mayer argued that the Paris Peace Conference was a struggle between what he calls the "Old Diplomacy" of the alliance system, secret treaties and brutal power politics and the "New Diplomacy" as represented by Vladmir Lenin's Peace Degrees of 1917 and Woodrow Wilson's Fourteen Points, which Mayer sees as promoting peaceful and rational diplomacy. Mayer argued that in 1919, the world was divided between the "forces of movement" behind the "New Diplomacy", representing liberal and left-wing forces and the "forces of order", representing conservative and reactionary forces behind the "Old Diplomacy" Mayer sees all foreign policy as basically a projection of domestic politics, and much of his writing on international relations is devoted towards explaining just what domestic lobby was exerting the most influnce on foreign policy at that particular moment of time" In Mayer's view, the "New Diplomacy" associated with Lenin and Wilson (whose 14 Points Mayer sees as a hasty liberal attempt to respond to Lenin's Peace Degrees) was associated with Russia and America, both societies that Mayer has argued either had destroyed or lacked the partial "modernized" societies that characterized the rest of Europe Mayer sees US diplomacy at Versailles as an attempt to posit a "new", but "counter-revolutionary" style of diplomacy against "revolutionary" Soviet diplomacy In Mayer's view, the greatest failure of the Versailles Treaty was that it was a triumph for the "Old Diplomacy" with a thin "New Diplomacy" veneer. The principal reason for this according to Mayer was he considered to be the irrational fears generated by the Russian Revolution, thus leading to an international system designed to contain the Soviet Union. A major influence on Mayer is the late British historian E. H. Carr. In 1961, Mayer played a key role in having an American edition of his friend and mentor's book, What is History? published. Many of Mayer's writings on international affairs in the interwar era take as their starting point Carr's 1939 book The Twenty Year's Crisis.

In his 1981 book, The Persistence of the Old Regime, Mayer argued that there was a "umbilical cord" linking all the events of European history from 1914 to 1945. In Mayer's opinion, World War I was proof that: "The forces of the old order were sufficiently willful and powerful to resist and slow down the course of history, if necessary by recourse to violence". Mayer argued that because of its ownership of the majority of the land in Europe and because the middle class were divided and politically undeveloped, the nobility continued as the dominant class in Europe. Mayer argued that faced with the challenge of a world in which they had lost their function, the aristocracy both embraced and promoted reactionary beliefs such as Nietzsche and Social Darwinism together with a belief in dictatorship and fascist dictatorship in particular. In Mayer's view, "It would take two world wars and the Holocaust...finally to dislodge the feudal and aristocratic presumption from Europe's civil and political societies".

In his 1988 book Why Did the Heavens Not Darken? Mayer argues that Adolf Hitler ordered the Final Solution in December 1941 in response to the realisation that the Wehrmacht could not take Moscow, hence ensuring Nazi Germany's defeat at the hands of the Soviet Union. In Mayer's opinion, the "Judeocide", as Mayer calls the Holocaust was the horrific climax of the “Thirty Years' Crisis” that had been raging in Europe since 1914.

The Holocaust, which Mayer refers to as the "Judeocide", is viewed by him primarily an expression of anti-communism. In his book, Mayer wrote:

"Anti-Semitism did not play a decisive or even significant role in the growth of the Nazi movement and electorate. The appeals of Nazism were many and complex. People rallied to a syncretic creed of ultra-nationalism, Social Darwinism, anti-Marxism, anti-bolshevism, and anti-Semitism, as well as to a party programs calling for the revision of Versailles, the repeal of reparations, the curb of industrial capitalism, and the establishment of a völkisch welfare state"

Mayer's purpose in writing Why Did the Heavens Not Darken? was in his words to put an end to "cult of remembrance", which in his view had "become overly sectarian" with too much focus on Jewish suffering and on the Jewish dead Mayer has often accused Israel of exploiting the memory of the Holocaust to further its foreign policy objectives In Mayer's opinion, Hitler's war first and foremost against the Soviets, not the Jews. According to Mayer, the original German plan was after the German victory over the Soviet Union to deport all the Soviet Jews to a reservation behind the Urals

In regards to the functionalist-intentionalist divide that pervades Holocaust historiography, Mayer's work can be seen as a bridge between the two schools. Mayer argues that there was no masterplan for genocide, and that the Holocaust cannot be explained solely in regards to Hitler's world-view. At the same time, Mayer agrees with those intentionalist historians such as Andreas Hillgruber (with whom Mayer otherwise has little in common with) in seeing Operation Barbarossa, and the Nazi crusade to annihilate "Judeo-Bolshevism" as the key development in the genesis of the "Final Solution to the Jewish Question".

Why Did the Heavens Not Darken? met with generally critical reviews in 1988. The British historian Richard J. Evans, in summing up U.S. reviews of the book, noted that some of the more "printable" responses by U.S. historians included: "a mockery of memory and history" and "bizarre and perverse." Reviewers criticized Mayer's account of the Holocaust as focused too heavily on Nazi anti-communism at the expense of a focus on antisemitism.

Two critics of Why Did the Heavens Not Darken? were U.S. historians Daniel Goldhagen and Lucy Dawidowicz. Both questioned Mayer's account of the murder of Jews during the early phases of World War II, arguing the organised and systemic role played by the Nazis was much greater. Both accused Mayer of attempting to rationalize the Holocaust, comparing him to ultra right-wing historians such as Ernst Nolte. The Israeli historian Yehuda Bauer wrote that Mayer "...popularizes the nonsense that the Nazis saw in Marxism and Bolshevism their main enemy, and the Jews unfortunately got caught up in this; when he links the destruction of the Jews to the ups and downs of German warfare in the Soviet Union, in a book that is so cocksure of itself that it does not need a proper scientific apparatus, he is really engaging in a much subtle form of Holocaust denial"

Holocaust deniers have often quoted out of context Mayer’s sentence in Why Did the Heavens Not Darken? that “Sources for the study of the gas chambers at once rare and unreliable” As the authors Michael Shermer and Alex Grobman have noted, the entire paragraph from which the sentence comes from states that the SS destroyed the majority of the documention relating to the operation of the gas chambers in the death camps, which is why Mayer feels that sources for the operation of the gas chambers are "rare" and "unreliable" One of Mayer's leading defenders, the journalist D.D. Guttenplan wrote in Mayer's defense that he believed that there was much to Mayer's thesis about the Holocaust as a result of the Nazi obsession with "Judeo-Bolshevism", and that Mayer had been unjustly and harshly treated by a conservative U.S. Jewish establishment and by anti-communist historians.

The American historian Peter Baldwin noted certain parallels between Mayer’s views in Why Did the Heavens Not Darken? and those expressed by the German radical right-wing historian Ernst Nolte. Baldwin noted that both see the inter-war period as one of intense ideological conflict between the forces of the Right and Left, that World War II was the culmination of this conflict, and both see the Holocaust as a by-product of the German-Soviet war. However, Baldwin went to note the central difference between Nolte and Mayer in that for the former the Soviets were aggressors who essentially got what they deserved in the form of Operation Barbarossa while for the latter the Soviets were victims of a monstrous regime. Much of the controversy around Why Did the Heavens Not Darken? was due to the simple fact that through this book the general public first learned of the functionalist view that there was no masterplan for the Holocaust going back to the days when Hitler wrote Mein Kampf. In Baldwin's opinion, Goldhagen and others were probably right in criticizing Mayer's view about the timing of the decision to launch the Holocaust; on the other hand, Baldwin considered that Goldhagen missed Mayer's overall point about the connection between the war against the Soviet Union and the Holocaust. Another area of controversy centered around Mayer’s claim that most of the Jews who died at Auschwitz were the victims of diseases, rather than mass gassings, a claim that has been cited by David Irving as one of his reasons for embracing Holocaust denial. The Dutch-Canadian architectural expert Robert Jan van Pelt has noted that Mayer's book with its claim that there were more "natural" then "unnatural" deaths at Auschwitz is as close as a mainstream historian has ever come to supporting Holocaust denial. The U.S. journalist D.D. Guttenplan, who was otherwise highly sympathetic towards Mayer's theory of the Soviet citizens (Jewish and non-Jewish) and Jews in general, as fellow victims of the Holocaust, called this statement "indefensible".

Mayer has been critical of the policies of the United States government. As a Marxist, Mayer has stated in a 2001 essay that "since 1947 America has been the chief and pioneering perpetrator of 'preemptive' state terror, exclusively in the Third World and therefore widely dissembled." Mayer's latest book, Plowshares into Swords is an anti-Zionist and pro-Palestinian account of Israeli history, tracing what Mayer regards as the degradation and denegation of Jewry in general and Zionism in particular in face of what Mayer sees as Israeli colonial aggression against the Palestinians. In a favorable review, the British writer Geoffrey Wheatcroft called Plowshares into Swords an enlightening account of Israeli history that traced the "...chauvinistic and brutalising tendencies of Zionism". In a hostile review of Plowshares into Swords, the British scholar Simon Goldhill called Plowshares into Swords a book of little value and criticzed Mayer for his anti-Israeli bias, arguing that Mayer ignored Arab anti-Semitism, falsely portrayed the Six Day War as an imperialist power play by the United States, for claiming that all Western criticism of the Islamic world is self-interested, and for describing anti-Western feeling in the Arab world as "righteous anger"