Edward Everett Horton was born in Brooklyn, New York. He was named for his grandfather, Edward Everett Hale, who was the nephew and namesake of orator and presidential candidate Edward Everett. Horton attended Brooklyn Polytechnic and Columbia University, where he was a member of Phi Kappa Psi Fraternity.

Horton started his stage career in 1906, singing and dancing and playing small parts in Vaudeville and in Broadway productions. In 1919 he moved to Los Angeles, California, and started getting roles in Hollywood films. His first starring role was in the 1922 comedy film Too Much Business. After a few years he began being cast as a character actor in supporting roles. Some of his noteworthy films include The Front Page, Trouble in Paradise, Top Hat, Holiday, Lost Horizon, Here Comes Mr. Jordan, Pocketful of Miracles, and Arsenic and Old Lace.

In the 1950s Horton started doing television work. Many who were young in the 1960s remember him as the narrator for the "Fractured Fairy Tales" segment of the Rocky & Bullwinkle cartoon show. Later he played Chief Roaring Chicken in the sitcom F Troop. His last role, as a moribund tobacco company president in a wheelchair, was in the motion picture Cold Turkey, released after his death.

Edward Everett Horton died of cancer at age 84 in Encino, California.