Michener graduated from Doylestown High School in 1925. He attended Swarthmore College, in Swarthmore, Pennsylvania, where he played basketball and was a member of the Phi Delta Theta fraternity. After graduating summa cum laude in 1929, with a Bachelor of Arts degree in English and History, he traveled and studied in Scotland at the University of St Andrews in the medieval town of St. Andrews, Fife on the coast of the North Sea for two years.

Michener took a job as a high school English Teacher at The Hill School in Pottstown, Pennsylvania. From 1933 to 1936, he taught English at George School in Newtown, Pennsylvania. He attended Colorado State College of Education in Greeley, Colorado, (in 1970 renamed the University of Northern Colorado), where he earned a Master of Arts degree in Education. After graduation, he taught at the university and at College High School (the University Lab School) for several years. The library at the University of Northern Colorado was named after him in October 1972.

Michener was married three times. In 1935, he married Patti Koon. In 1948, they divorced, and the same year Michener married his second wife, Vange Nord.

Michener was called to active duty during World War II (1941–1945) in the United States Navy. He traveled throughout the South Pacific Ocean on various assignments which he gained because his base commanders mistakenly thought his father was Admiral Marc Mitscher. His experiences during these travels inspired the stories published in his breakout work Tales of the South Pacific.

Michener began his writing career during World War II, when as a lieutenant in the U.S. Navy he was assigned to the South Pacific as a naval Historian. He later turned his notes and impressions into Tales of the South Pacific (1947), his first book, published when he was age 40. It won the Pulitzer Prize for fiction in 1948, and Rodgers and Hammerstein adapted it as the hit Broadway musical South Pacific, which premiered on Broadway in New York City in 1949. The musical was also adapted as eponymous feature films in 1958 and 2001.

Michener's novels include Tales of the South Pacific for which he won the Pulitzer Prize for Fiction in 1948, Hawaii, The Drifters, Centennial, The Source, The Fires of Spring, Chesapeake, Caribbean, Caravans, Alaska, Texas, and Poland. His non-fiction works include Iberia, about his travels in Spain and Portugal; his memoir titled The World Is My Home; and Sports in America. Return to Paradise combines fictional short stories with Michener's factual descriptions of the Pacific areas where they take place.

In the late 1950s, Michener began working as a roving Editor for the Readers' Guide to Periodical Literature. He gave up that work in 1970.

Michener's novel Sayonara (1954) is quasi-autobiographical. Set during the early 1950s, it tells the story of Major Lloyd Gruver, a United States Air Force ace jet pilot in the Korean War (1950–1953), now stationed in Japan, who falls in love with Hana-Ogi, a Japanese woman. The novel follows their cross-cultural romance and illuminates the racism of the post-World War II time period. It also was adapted into a highly successful 1957 movie of the same name, starring Marlon Brando, James Garner, Miiko Taka, and Red Buttons, who won the 1958 Academy Award ("Oscar") for best supporting actor.

Michener met his third wife, Mari Yoriko Sabusawa, at a luncheon in Chicago. An American, she and her Japanese parents had suffered internment in western camps that the U.S. government set up during the early years of World War II to hold ethnic Japanese from West Coast / Pacific communities. Michener divorced Nord in 1955 and married Sabusawa the same year. Sabusawa died in 1994.

His first book was adapted as the popular Broadway musical South Pacific by Richard Rodgers and Oscar Hammerstein, and later as eponymous feature films in 1958 and 2001, adding to his financial success. He also wrote an analysis of the United States' Electoral College system in a book which condemned it, entitled Presidential Lottery: The Reckless Gamble in Our Electoral System. It was published in 1969, and republished in 2014 and 2016.

Michener was a popular Writer during his lifetime; his novels sold an estimated 75 million copies worldwide. His novel Hawaii (1959), well-timed on its publication when Hawaii became the 50th state, was based on extensive research. He used this approach for nearly all of his subsequent novels, which were based on detailed historical, cultural, and even geological research. Centennial (1974), which documented several generations of families in the Rocky Mountains of the American West, was adapted as a popular 12-part television miniseries of the same name and aired on the National Broadcasting Company (NBC television network) from October 1978 through February 1979.

In 1960, Michener was chairman of the Bucks County committee to elect Democrat John F. Kennedy as the 35th President. In 1962, he unsuccessfully ran as a Democratic Party candidate for a seat in the U.S. House of Representatives from Pennsylvania, a decision he later considered a misstep. "My mistake was to run in 1962 as a Democratic candidate for Congress. [My wife] kept saying, 'Don't do it, don't do it.' I lost and went back to writing books."

In 1968, Michener served as the campaign manager for the third-term run of the twice-elected U.S. Senator Joseph S. Clark of Pennsylvania. Michener later served as Secretary for the 1967–1968 Pennsylvania Constitutional Convention. Also that year, Michener was a member of the Electoral College, serving as a Pennsylvania Democrat. He wrote about that experience in a political science text Presidential Lottery: The Reckless Gamble in Our Electoral System, which was published the following year. In it, he suggested alternate systems, including using a direct popular vote by majority for the office of President of the United States.

Opened in 1988, in Michener's hometown of Doylestown, Pennsylvania, the James A. Michener Art Museum houses collections of local and well-known artists. Michener pledged $5.5 million to the museum in 1996. Constructed from the remains of an old state prison, the museum is a non-profit organization with both permanent and rotating collections. Two prominent permanent fixtures are the James A. Michener display room and the Nakashima Reading Room, constructed in honor of his third wife's Japanese heritage. The museum is known for its permanent collection of Pennsylvania Impressionist paintings.

In 1989, Michener donated the royalty earnings from the Canadian edition of his novel Journey (1989), published in Canada by McClelland & Stewart, to create the Journey Prize, an annual Canadian literary prize worth $10,000 (CDN) that is awarded for the year's best short story published by an emerging Canadian Writer.

Michener became a major philanthropist, donating more than $100 million to educational, cultural, and writing institutions, including his alma mater, Swarthmore College, the Iowa Writers Workshop, and the James A. Michener Art Museum, and more than $37 million to University of Texas at Austin. By 1992, his gifts made him UT Austin's largest single donor to that time. Over the years, Mari Michener played a major role in helping direct his donations.

In 1996, State House Press published James A. Michener: A Bibliography, compiled by David A. Groseclose. Its more than 2,500 entries from 1923 to 1995 include magazine articles, forewords, and other works.

Suffering from terminal kidney disease, in October 1997, Michener ended the daily dialysis treatment that had kept him alive for four years. He said he had accomplished what he wanted and did not want further physical complications. On October 16, 1997, he died of kidney failure, at age 90. Michener was cremated, and his ashes were placed next to those of his wife at Austin Memorial Park Cemetery in Austin, Texas.

The James A. Michener Society was formed in the fall of 1998. It comprises people who share a Common interest and admirers of Michener's life and work. The society sponsors a variety of activities and publishes an electronic internet newsletter. Annual meetings of members are held at locations closely associated with Michener's life. The society's purpose is to: