Born in Salford, Lancashire, England, his father was a lay Methodist preacher and metalsmith by trade; his mother's family were of Irish Protestant origin. Originally named Alfred, he changed his name to Alistair when he was 22. He was educated at Blackpool Grammar School, and won a scholarship to Jesus College, Cambridge, where he gained an honours degree (2:1) in English. He was heavily involved in the arts, was editor of Granta, and set up The Mummers, Cambridge's first co-sex theatre group, from which he notably rejected a young James Mason, telling him to stick to architecture.

Cooke became engaged to Henrietta Riddle, the daughter of Henry Ainley. However whilst he was attending Yale University and Harvard University on a Commonwealth fund fellowship, she deserted him. He met Ruth Emerson, a great-grandniece of Ralph Waldo Emerson, in 1933, and they married on 24 August 1934. Charlie Chaplin had agreed to be Cooke's best man, but he was a no-show at the ceremony. The couple had a son, John, who graduated from Harvard University and shortly thereafter (1966) became the road manager for Big Brother and the Holding Company. After the band's lead singer Janis Joplin started her own band with solo billing, John Cooke remained her road manager. He was her confidant at the time of her death in 1970.

Alistair Cooke divorced Ruth in 1944, and married Jane White Hawkes, a portrait painter and the widow of neurologist A. Whitfield Hawkes, the son of Albert W. Hawkes, on April 30, 1946. Their daughter, Susan, was born on 22 March 1949. The couple remained together until his death.

Cooke saw a newspaper headline that Oliver Baldwin, the Prime Minister Stanley Baldwin's son, had been fired by the BBC as film critic. Cooke sent a telegram to the Director of Talks, asking if he would be considered for the post. He was invited for interview and took a Cunard liner back to England, arriving twenty four hours late for his interview. He suggested typing out a film review on the spot, and a few minutes later, he was offered the job. He also sat on a BBC committee headed by George Bernard Shaw for correct pronunciation. The fact that Shaw spoke with a strong Dublin accent caused Cooke some amusement.

Cooke was also London correspondent for NBC. Each week, he recorded a 15-minute talk for American listeners on life in Britain, under the series title of London Letter. In 1936, he intensively reported on the Edward VIII abdication crisis for NBC. He made several talks on the topic each day to listeners in many parts of the United States. He calculated that in ten days he spoke 400,000 words on the subject. During the crisis, he was aided by a twenty-year-old Rhodes Scholar, Walt Rostow, who would become Lyndon B. Johnson's national security advisor.

In 1937, Cooke moved to the United States, starting what was to become a permanent emigration. He became US citizen and swore the Oath of Allegiance on 1 December 1941, six days before Pearl Harbor was attacked. Shortly after emigrating, Cooke suggested to the BBC the idea of doing the London Letter in reverse: a 15-minute talk for British listeners on life in America. A prototype, Mainly About Manhattan, was broadcast intermittently from 1938, but the idea was shelved with the outbreak of World War II in 1939. During the war, he broadcast a weekly American Commentary on the BBC about the war.

During this time, as well, Cooke undertook a journey through the whole United States, recording the lifestyle of ordinary Americans during the war – and their reactions to it. The manuscript did not arouse much interest immediately after the war, but it was discovered a few weeks before his death in 2004 and published as The American Home Front: 1941-1942 in the United States (and as Alistair Cooke's American Journey: Life on the Home Front in the Second World War in the UK) in 2006. Accompanied by strong reviews, it stands as the only incisive first-hand journal of the American home front ever published, even though the account is confined to the early stages of the war.

The first American Letter was broadcast on March 24, 1946 (Cooke said this was at the request of Lindsey Wellington, BBC's New York Controller); the series was initially commissoned for only 13 instalments. The series finally came to an end 58 years (2,869 installments) later, in March 2004. Along the way, it picked up a new name (changing from American Letter to Letter from America in 1950) and an enormous audience, being broadcast not only in Britain and in many other Commonwealth countries, but throughout the world by the BBC World Service. The original scripts are held at the BBC and at the Howard Gotlieb Archival Research Center of Boston University.

In 1991, Alistair Cooke received a special BAFTA silver award for his contribution to Anglo-American relations.

In 1947, Cooke became a foreign correspondent for the Manchester Guardian newspaper (later The Guardian), for which he wrote until 1972. It was the first time he had been employed as a staff reporter; all his previous work had been freelance. He also served as a foreign correspondent for The Times.

In 1952, Cooke became the host of CBS's Omnibus, the first commercial network television series devoted to the arts. It featured appearances by such personalities as Hume Cronyn, Jessica Tandy, Gene Kelly, and Leonard Bernstein. Jonathan Winters was the first comic to appear on the show. The series marked Bernstein's first-ever television appearances.

Cooke took up golf in his mid-fifties, developing a pronounced fascination with the game, despite never attaining an extraordinary level of skill. He was driven by his love of golf to devote many of his Letters from America to the topic, speaking one of the thrill of learning 'how much more awesome was the world of golf than the world of politics'. Cooke became close friends with many of the leading golfers of the era: Jack Nicklaus, in the introduction to a compilation of Cooke's writing on golf, recounts his many notable achievements, but describes him as 'most of all... a friend.'

In 1968, he was only yards away from Robert F. Kennedy when he was assassinated, witnessing the events that followed.

In 1971, he became the host of the new Masterpiece Theatre, PBS's showcase of quality British television. He remained its host for 22 years, before retiring from the role in 1992. He achieved his greatest popularity in the U.S. in this role, becoming the subject of many parodies, including "Alistair Cookie" in Sesame Street's "Monsterpiece Theater" ("Alistair Cookie" was also the name of a clay animated cookie-headed spoof character created by Will Vinton as the host of a video trailer for The Little Prince and Friends); Alistair Quince, from The Carol Burnett Show, introducing the "The Family" sketches, which eventually became Mama's Family; and, arguably, Leonard Pinth-Garnell, in Saturday Night Live's "Bad Conceptual Theatre".

A Personal History of the United States (1972), a 13-part television series about the United States and its history, was first broadcast in both the United Kingdom and the United States in 1973, and was followed by a book of the same title. It was a great success in both countries, and resulted in Cooke's being invited to address the joint Houses of the United States Congress as part of Congress's bicentennial celebrations. After the series' broadcast in Ireland, Cooke won a Jacob's Award, one of the few occasions when this award was made to the maker of an imported programme. Alistair Cooke said that, of all his work, America was that of which he was most proud; it is the result and expression of his long love of America. Asked once how long it took him to make the series, Cooke replied, "I do not want to be coy, but it took 40 years."

Later the same year, Cooke was awarded an honorary knighthood (KBE) for his "outstanding contribution to Anglo-American mutual understanding." Cooke was reportedly happy to accept because in the words of Thomas Jefferson, it did not involve "the very great vanity of a title." Having relinquished his British citizenship during World War II, he could not be called "Sir Alistair". For more than 50 years, Cooke lived in a rent-controlled apartment in Manhattan, New York City, outliving several property owners and all fellow tenants.

On March 2, 2004, at the age of 95, following advice from his doctors, Cooke announced his retirement from Letter from America — after 58 years, the longest-running speech radio show in the world.

Cooke died at midnight on March 30, 2004, at his home in New York City. He had been ill with heart disease, but died of lung cancer, which had spread to his bones. He was cremated, and his ashes were clandestinely scattered by his family in Central Park.

On December 22, 2005, the New York Daily News reported that the bones of Cooke and many other people had been surgically removed before cremation by employees of Biomedical Tissue Services of Fort Lee, New Jersey, a tissue-recovery firm. The thieves allegedly sold the bones for use as medical-grade bone grafts. The cancer from which Cooke was suffering had spread to his bones, making them unsuitable for grafts. Reports indicated the people involved in selling the bones altered his death certificate to hide the cause of death and reduce his age from 95 to 85. Michael Mastromarino, a former New Jersey—based oral surgeon, and Lee Cruceta agreed to a deal that resulted in their imprisonment. Mastromarino was sentenced on June 27, 2008, in the Supreme Court in Brooklyn to 18 to 54 years' imprisonment. The entire story of the theft featured in a documentary aimed at educating the public about modern day grave robbery.

After Alistair Cooke's death the Fulbright Alistair Cooke Award in Journalism was established as a tribute to the man and his life and career achievements. The award supports students from the United Kingdom to undertake studies in the US and for Americans to study in the UK. It is offered for a Masters in Journalism or specialist study (e.g. Middle Eastern Studies) leading to a career in journalism.

The Fulbright Program, sponsored by the US Department of State Bureau of Educational and Cultural Affairs, was created in the aftermath of World War II through the efforts of US Senator J. William Fulbright.

UK recipients of the Fulbright Alistair Cooke Award are listed below.

2008-9 Simon Akam (Oxford University) and Dan Walker Smith (Edinburgh University)

2007-8 Peter Cardwell (Oxford University)

2006-7 Archie Bland (Cambridge University)

2005-6 Ewan Jones (Cambridge University)

• Douglas Fairbanks: The Making of a Screen Character (1940)
• Mencken (1955)
• A William March Omnibus: with an introduction by Alistair Cooke (1956)
• A Generation on Trial: The USA v. Alger Hiss (1982) ISBN 0-313-23373-X
• The Patient Has the Floor (1986) ISBN 1-55504-214-7
• Six Men (1995) ISBN 1-55970-317-2
• Fun & Games with Alistair Cooke: On Sport and Other Amusements (1996) ISBN 1-55970-327-X
• Memories of the Great and the Good (2000) ISBN 1-55970-545-0
• The American Home Front: 1941-1942 (2006) ISBN 0-87113-939-1
• Alistair Cooke's American Journey: Life on the Home Front in the Second World War (2006) ISBN 0-7139-9879-2

"America" books

• Talk about America
• Letter from America: The Early Years 1946—1968
• America Observed: From the 1940s to the 1980s/Ronald A. Wells
• Letters from America: The Americans, Letters from America and Talk About America
• One Man's America
• The Americans
• Alistair Cooke's America (2002)
• Letter from America: (1946—2004) (2004) ISBN 1-4000-4402-2
• The Marvellous Mania: Alistair Cooke on Golf (2007) ISBN 978-071399996-9

Cooke also co-authored several "coffee table" photo books.

A Personal History of the United States, a 13-part series on DVD, with a bonus where Cooke talks about his life.