Majoring in history and sociology, Donald earned his bachelor degree from Millsaps College in Jackson, Mississippi. He earned his PhD in 1946 under the eminent, leading Lincoln scholar, James G. Randall at the University of Illinois. Randall as a mentor had a big influence on Donald's life and career, and encouraged his protege to write his dissertation on Lincoln's law partner, William Herndon. The dissertation eventually became his first book, Lincoln's Herndon, published in 1948. The effect Randall had on Donald was later illustrated by the fact that he gave his only son the middle name Randall in honor of his former mentor. After graduating, he taught at Columbia University, Johns Hopkins and, from 1973, Harvard University. He also taught at Smith College, the University of North Wales, Princeton University, University College London and served as Harmsworth Professor of American History at Oxford University. At Johns Hopkins, Columbia, and Harvard he trained dozens of graduate students including Jean H. Baker, William J. Cooper, Jr., Michael Holt, Irwin Unger, and Ari Hoogenboom. He received the Pulitzer Prize twice (1961 and 1988), several honorary degrees, and served as president of the Southern Historical Association.

David H. Donald was the Charles Warren Professor of American History (emeritus from 1991) at Harvard University. He wrote over thirty books, including well received biographies of Abraham Lincoln, Thomas Wolfe and Charles Sumner. He specialized in the Civil War and Reconstruction periods, and in the history of the South.

He is best known for his biography of Abraham Lincoln, which has been praised by Eric Foner as the best biography of Lincoln, and by Bill Clinton who called it "one of the best biographies on any person in politics," as well as his Pulitzer-Prize winning biographies of politician Charles Sumner and writer Thomas Wolfe. Weaving in a wealth of new historical material, he also revised his former mentor's classic textbook, Civil War and Reconstruction (1961, 2001).

Donald's first book Lincoln's Herndon (1948) was a biography of William Herndon, the junior partner in Abraham Lincoln's law firm in Springfield, Illinois. Herndon was Lincoln's trusted aide until Lincoln became president and, in 1889 published a highly controversial biography of Lincoln based on numerous interviews. Donald concluded that Herndon, "stands, in the backward glance of history, as myth-maker and truth-teller." In his introduction, Carl Sandburg, the poet and Lincoln biographer, hailed Donald's book as the answer to scholars' prayers: “When is someone going to do the life of Bill Herndon. Isn't it about time? Now the question is out.” David M. Potter, whose own credentials as a Lincoln scholar gave his words authority, said Donald's biography of Charles Sumner portrayed, "Sumner as a man with acute psychological inadequacies” and exposed Sumner's "facade of pompous rectitude." Donald's evenhanded approach to Sumner, Potter concluded, was a model for biographers working with a difficult subject. "If it does not make Sumner attractive [the book] certainly makes him understandable."

Donald argued that the American Civil War was a needless war caused or hastened by the fanaticism of people like Charles Sumner though he admires Abraham Lincoln.

Donald lived in Lincoln, Massachusetts, with his wife Aida DiPace Donald. He died of heart failure in Boston on May 17, 2009. Donald is survived by his son, Bruce Randall Donald, and his wife.