MacLeish was born in Glencoe, Illinois. His father, Andrew MacLeish, worked as a dry-goods merchant. His mother, Martha Hillard, was a college professor and had served as president of Rockford College. He grew up on an estate bordering Lake Michigan. He attended the Hotchkiss School from 1907 to 1911 before moving on to Yale University, where he majored in English, was elected to Phi Beta Kappa and selected for the Skull and Bones society. He then enrolled in the Harvard Law School. In 1916, he married. His studies were interrupted by World War I, in which he served first as an ambulance driver and later as a captain of artillery. He graduated from the law school in 1919. He taught law for a semester for the government department at Harvard, then worked briefly as an editor for The New Republic. He next spent three years practicing law.

In 1923 MacLeish left his law firm and moved with his wife to Paris, France, where they joined the community of literary expatriates that included such members as Gertrude Stein and Ernest Hemingway. They also became part of the famed coterie of Riviera hosts Gerald and Sarah Murphy, which included Hemingway, Zelda and F. Scott Fitzgerald, John Dos Passos Fernand Léger, Jean Cocteau, Pablo Picasso, John O'Hara, Cole Porter, Dorothy Parker and Robert Benchley. He returned to America in 1928. From 1930 to 1938 he worked as a writer and editor for Fortune Magazine, during which he also became increasingly politically active, especially with anti-fascist causes.

According to the American Libraries, "MacLeish is one of the hundred most influential figures in librarianship during the 20th century" in the United States. MacLeish’s career in libraries as well as public service began, not with a burning desire from within, but from a combination of the urging of a close friend Felix Frankfurter, and as MacLeish put it, “The President decided I wanted to be Librarian of Congress.” Franklin Roosevelt’s nomination of MacLeish was a controversial and highly political maneuver fraught with several challenges. First, the current Librarian of Congress, Herbert Putnam, who had served at the post for 40 years, needed to be persuaded to retire from the position. In order to be persuaded, Putnam was made Librarian Emeritus. Secondly, Franklin D. Roosevelt desired someone with similar political sensibilities to fill the post and to help convince the American public that the New Deal was working and that he had the right to run for an unprecedented third term in office. MacLeish’s occupation as a poet and his history as an expatriate in Paris rankled many Republicans. Lastly, MacLeish’s lack of a degree in library sciences or any training whatsoever aggravated the librarian community, especially the American Library Association which was campaigning for one of its members to be nominated. Despite these challenges, President Roosevelt and Justice Frankfurter felt that the mixture of MacLeish’s love for literature and his abilities to organize and motivate people, exemplified by his days in law school, would be just what the Library of Congress needed.

MacLeish sought support from expected places such as the president of Harvard, MacLeish’s current place of work, but found none. It was support from unexpected places, such as M. Llewellyn Raney of the University of Chicago libraries, which alleviated the ALA letter writing campaign against MacLeish’s nomination. Raney pointed out to the detractors that, “MacLeish was a lawyer like Putnamhe was equally at home in the arts as one of the four leading American poets now aliveand while it was true that he had not attended a professional school of library science, neither had thirty-four of thirty-seven persons presently occupying executive positions at the Library of Congress.” The main Republican arguments against MacLeish’s nomination from within Congress was: that he was a poet and was a “fellow traveler” or sympathetic to communist causes. Calling to mind differences with the party he had over the years, MacLeish avowed that, “no one would be more shocked to learn I am a Communist than the Communists themselves.” In Congress MacLeish’s main advocate was Senate Majority Leader Alben Barkley, Democrat from Kentucky. With President Roosevelt’s support and Senator Barkley’s skillful defense in the United States Senate, victory in a roll call vote with sixty-three Senators voting in favor of MacLeish’s appointment was achieved.

MacLeish found the Library of Congress to be extremely disorganized, as might be expected after being run by someone for forty years constantly trying to increase the size of the collection. MacLeish became privy to Roosevelt’s views on the library during a private meeting with the president. According to Roosevelt, the pay levels were too low and many people would need to be removed. Soon afterward, MacLeish joined Putnam for a luncheon in New York. At the meeting, Putnam relayed his desire to come to the Library for work and that his office would be down the hall from MacLeish’s. This meeting further crystallized for MacLeish that as Librarian of Congress, he would be “an unpopular newcomer, disturbing the status quo.”

It was a question from MacLeish’s daughter, Mimi, which led him to realize that, “Nothing is more difficult for the beginning librarian than to discover what profession he was engaged.” Mimi, his daughter, had inquired about what her daddy was to do all day, “hand out books?” Similar to any incoming executive to a new position, MacLeish created his own job description and set out to learn about how the library was currently organized. In October 1944, MacLeish described that he did not set out to reorganize the library, rather “one problem or another demanded action, and each problem solved led on to another that needed attention.”

MacLeish’s chief accomplishments had their start in instituting daily staff meetings with division chiefs, the chief assistant librarian, and other administrators. He then set about setting up various committees on various projects including: acquisitions policy, fiscal operations, cataloging, and outreach. The committees alerted MacLeish to various problems throughout the library.

First and foremost, under Putnam, the library was acquiring more books than it could catalog. A report in December 1939, found that over one-quarter of the library’s collection had not yet been cataloged. MacLeish solved the problem of acquisitions and cataloging through establishing another committee instructed to seek advice from specialists outside of the Library of Congress. The committee found many subject areas of the library to be adequate and many other areas to be, surprisingly, inadequately provided for. A set of general principles on acquisitions was then developed to ensure that, though it was impossible to collect everything, the Library of Congress would acquire the bare minimum of canons to meet its mission. These principles included acquiring, all materials necessary to members of Congress and government officers, all materials expressing and recording the life and achievements of the people of the United States, and materials of other societies past and present which are of the most immediate concern to the peoples of the United States.

Secondly, MacLeish set about reorganizing the operational structure. Leading scholars in library science were assigned a committee to analyze the library’s managerial structure. The committee issued a report a mere two months after it was formed, in April 1940 stating that a major restructuring was necessary. This was no surprise to MacLeish who had thirty-five divisions under him. He divided the library’s functions into three departments: administration, processing, and reference. All existing divisions were then assigned as appropriate. By including library scientists from inside and outside the Library of Congress, MacLeish was able to gain faith from the library community that he was on the right track. Within a year MacLeish had completely restructured the Library of Congress making it work more efficiently, bringing the library to the center to “report on the mystery of things.”

Last, but not least, MacLeish promoted the Library of Congress through various forms of public advocacy. Perhaps his greatest display of public advocacy was requesting a budget increase of over a million dollars in his March 1940 budget proposal to the United States Congress. While the library did not receive the full increase, it did receive an increase of $367, 591, the largest one-year increase to date. Much of the increase went toward improved pay levels, increased acquisitions in under served subject areas, and new positions.

During World War II MacLeish also served as director of the War Department's Office of Facts and Figures and as the assistant director of the Office of War Information. These jobs were heavily involved with propaganda, which was well-suited to MacLeish's talents; he had written quite a bit of politically motivated work in the previous decade. He spent a year as the Assistant Secretary of State for Public Affairs and a further year representing the U.S. at the creation of UNESCO. After this, he retired from public service and returned to academia.

Despite a long history of criticizing Marxism, MacLeish came under fire from conservative politicians of the 1940s and 1950s, including J. Edgar Hoover and Joseph McCarthy. Much of this was due to his involvement with anti-fascist organizations like the League of American Writers, and to his friendships with prominent left-wing writers. In 1949 MacLeish became the Boylston Professor of Rhetoric and Oratory at Harvard. He held this position until his retirement in 1962. In 1959 his play J.B. won the Pulitzer Prize for Drama. From 1963 to 1967 he was the John Woodruff Simpson Lecturer at Amherst College. Around 1969/70 he met Bob Dylan, who describes this encounter in the third chapter of Chronicles, Vol. 1.

MacLeish greatly admired T. S. Eliot and Ezra Pound, and his work shows quite a bit of their influence. In fact, some critics charge that his poetry is derivative and adds little of MacLeish's own voice . MacLeish's early work was very traditionally modernist and accepted the contemporary modernist position holding that a poet was isolated from society. His most well-known poem, "Ars Poetica," contains a classic statement of the modernist aesthetic: "A poem should not mean / But be." He later broke with modernism's pure aesthetic. MacLeish himself was greatly involved in public life and came to believe that this was not only an appropriate but an inevitable role for a poet.

MacLeish worked to promote the arts, culture, and libraries. Among other impacts, MacLeish was the first Librarian of Congress to begin the process of naming what would become the United States Poet Laureate. The Poet Laureate Consultant in Poetry to the Library of Congress came from a donation in 1937 from Archer M. Huntington, a wealthy ship builder. Like many donations it came with strings attached. In this case Huntington wanted the poet Joseph Auslander to be named to the position. MacLeish found little value in Auslander’s writing. However, MacLeish was happy that having Auslander in the post attracted many other poets, such as Robinson Jeffers and Robert Frost, to hold readings at the library. He set about establishing the consultantship as a revolving post rather than a lifetime position. In 1943, MacLeish displayed his love of poetry and the Library of Congress by naming Louise Bogan to the position. Bogan, who had long been a hostile critic of MacLeish’s own writing, asked MacLeish why he appointed her to the position; MacLeish replied that she was the best person for the job. For MacLeish promoting the Library of Congress and the arts was vitally more important than petty personal conflicts.

In the June 5, 1972 issue of The American Scholar, MacLeish laid out in an essay his philosophy on libraries and librarianship, further shaping modern thought on the subject. MacLeish remarked in the essay that libraries are more than a mere collection of books. "If books are reports on the mysteries of the world and our existence in it, libraries remain reporting on the human mind, that particular mystery, still remains as countries lose their grandeur and universities are not certain what they are." For MacLeish, libraries are a massive report on the mysteries of human kind.

Two collections of MacLeish's papers are held at the Beinecke Rare Book and Manuscript Library: these are the Archibald MacLeish Collection (YCAL MSS 38) and Archibald MacLeish Collection Addition (YCAL MSS 269).