Schlesinger was born in Columbus, Ohio, the son of Elizabeth Harriet (née Bancroft) and Arthur M. Schlesinger (1888–1965), who was an influential social Historian at Ohio State University and Harvard University, where he directed many PhD dissertations in American history. His paternal grandfather was a Prussian Jew who converted to Protestantism and then married an Austrian Catholic. His mother, a Mayflower descendant, was of German and New England ancestry, as well as a relative of Historian George Bancroft, according to family tradition. His family practiced Unitarianism.

Schlesinger attended the Phillips Exeter Academy, New Hampshire, and received his first degree at the age of 20 from Harvard College, where he graduated summa cum laude in 1938. After spending the 1938–1939 academic year at Peterhouse, Cambridge as a Henry Fellow, he was appointed to a three-year Junior Fellowship in the Harvard Society of Fellows in the fall of 1939. At the time, Fellows were not allowed to pursue advanced degrees, "a requirement intended to keep them off the standard academic treadmill"; as such, Schlesinger would never earn a doctorate. His fellowship was interrupted by the United States entering World War II. After failing his military medical examination, Schlesinger joined the Office of War Information. From 1943 to 1945, he served as an intelligence analyst in the Office of Strategic Services, a precursor to the CIA.

He won a Pulitzer Prize for History in 1946 for his book The Age of Jackson, covering the intellectual environment of Jacksonian democracy. He won a second Pulitzer in the Biography category in 1966 for A Thousand Days.

In 1947, Schlesinger, together with former First Lady Eleanor Roosevelt, Minneapolis mayor and Future Senator and Vice President Hubert Humphrey, Economist and longtime friend John Kenneth Galbraith, and Protestant theologian Reinhold Niebuhr, founded Americans for Democratic Action. Schlesinger acted as the ADA's national chairman from 1953 to 1954.

His 1949 book The Vital Center made a case for the New Deal policies of Franklin D. Roosevelt and was harshly critical of both unregulated capitalism and of those liberals such as Henry A. Wallace who advocated coexistence with communism.

Schlesinger had known John F. Kennedy since attending Harvard and increasingly socialized with Kennedy and his wife Jacqueline in the 1950s. In 1954, the Boston Post publisher John Fox Jr. had planned series of newspaper pieces labeling several Harvard figures, including Schlesinger, as "reds", Kennedy intervened on Schlesinger's behalf, which Schlesinger recounted in A Thousand Days.

After President Harry S. Truman announced he would not run for a second full term in the 1952 presidential election, Schlesinger became the primary speechwriter for and an ardent supporter of Governor Adlai E. Stevenson of Illinois. In the 1956 election, Schlesinger, along with 30-year-old Robert F. Kennedy, again worked on Stevenson's campaign staff. Schlesinger supported the nomination of Massachusetts Senator John F. Kennedy, as Stevenson's vice-presidential running mate, but at the Democratic convention, Kennedy came second in the vice-presidential balloting, losing to Senator Estes Kefauver of Tennessee.

Throughout the 1960s and 1970s, he greatly criticized Richard Nixon as both a candidate and President. His prominent status as a liberal Democrat and outspoken disdain of Nixon led to his placement on the master list of Nixon's political opponents. Ironically, Nixon would become his next-door neighbor in the years following the Watergate scandal.

In February 1961, Schlesinger was first told of the "Cuba operation," which would eventually become the Bay of Pigs Invasion. He opposed the plan in a memorandum to the president: "at one stroke you would dissipate all the extraordinary good will which has been rising toward the new Administration through the world. It would fix a malevolent image of the new Administration in the minds of millions." He, however, suggested,

In his book The Politics of Hope (1962), Schlesinger terms conservatives the "party of the past" and liberals "the party of hope" and calls for overcoming the division between both parties.

After President Kennedy was assassinated on November 22, 1963, Schlesinger resigned his position in January 1964. He wrote a memoir/history of the Kennedy administration, A Thousand Days: John F. Kennedy in the White House, which won him his second Pulitzer Prize in 1965.

Schlesinger returned to teaching in 1966 as the Albert Schweitzer Professor of the Humanities at the Graduate Center of The City University of New York. After his retirement from teaching in 1994, he remained an active member of the Graduate Center community as an emeritus professor until his death.

After his Service for the Kennedy administration, he continued to be a Kennedy loyalist for the rest of his life, campaigning for Robert Kennedy's tragic presidential campaign in 1968 and for Senator Edward M. Kennedy in 1980. Upon the request of Robert Kennedy's widow, Ethel Kennedy, he wrote the biography Robert Kennedy and His Times, which was published in 1978.

He became a leading opponent of multiculturalism in the 1980s and articulated this stance in his book The Disuniting of America (1991).

His 1986 book The Cycles of American History was an early work on cycles in politics in the United States; it was influenced by his father's work on cycles.

After he retired from teaching, he remained involved in politics for the rest of his life through his books and public speaking tours. Schlesinger was a critic of the Clinton Administration, resisting President Clinton's cooptation of his "Vital Center" concept in an article for Slate in 1997. Schlesinger was also a critic of the 2003 Iraq War and called it a misadventure. He put much blame on the media for not covering a reasoned case against the war.

Besides writing biographies he also wrote a foreword to a book on Vladimir Putin which came out in 2003 under the same name and was published by Chelsea House Publishers.

Published posthumously in 2007, Journals 1952–2000 is the 894-page distillation of 6,000 pages of Schlesinger diaries on a wide variety of subjects, edited by Andrew and Stephen Schlesinger.

Schlesinger's Service in the OSS allowed him time to complete his first Pulitzer Prize–winning book, The Age of Jackson, in 1945. From 1946 to 1954, he was an associate professor at Harvard, becoming a full professor in 1954.