Though he considered Danville, Illinois to be his home town, O’Connor was born in St. Elizabeth Hospital in Chicago. His parents, Effie Irene (née Crane) and John Edward “Chuck” O’Connor, were vaudeville entertainers. His father’s family was from County Cork, Ireland. When O’Connor was only a few years old, he and his sister Arlene were in a car crash outside a theater in Hartford, Connecticut; O’Connor survived, but his sister was killed. Several weeks later, his father died of a heart attack while dancing on stage in Brockton, Massachusetts. O’Connor at the time was being held in the arms of the theater manager, Mr. Morris Simms. O’Connor began performing in movies in 1937. He appeared opposite Bing Crosby in Sing You Sinners at age 12. Paramount Pictures used him in both A and B films, including Tom Sawyer, Detective and Beau Geste. In 1940, when he had outgrown child roles, he returned to vaudeville. In 1941, O’Connor signed with Universal Pictures, where he began by appearing in seven B-picture musicals in a row, starting with What’s Cookin’? (1942) and ending with Mister Big (1943). Peggy Ryan and Gloria Jean were in four each. Before Mister Big (1943) was released, O’Connor’s popularity soared. Universal added $50,000 in musical numbers to Mister Big (1943) and promoted this B movie to an A. His subsequent films were all A’s. On his 18th birthday in August, 1943, during World War II O’Connor was drafted into the United States Army. Before he reported for induction on Feb. 6, 1944, Universal already had four O’Connor films completed. They rushed production to complete three more by that date. With a backlog of seven features, deferred openings kept O’Connor‘s screen presence uninterrupted during the two years he was overseas. Upon his return, a merger in 1946 had reorganized the studio as Universal-International.

In 1949, he played the lead role in Francis, the story of a soldier befriended by a talking mule. The film was a huge success. As a consequence, his musical career was constantly interrupted by production of one Francis film per year until 1955. It was because of the Francis series that O’Connor missed playing Bing Crosby’s partner in White Christmas. O’Connor was unavailable because he contracted an illness transmitted by the mule, and was replaced in the film by Danny Kaye. O’Connor’s role as Cosmo the piano player in Singin’ in the Rain earned him a Golden Globe Award for Best Performance by an Actor in a Comedy or Musical. The film featured his memorable rendition of Make ‘Em Laugh. O’Connor said he smoked 4 packs of cigarettes a day during filming. O’Connor was a regular host of NBC’s Colgate Comedy Hour. He hosted a color television special on NBC in 1957, one of the earliest color programs to be preserved on a color kinescope; an excerpt of the telecast was included in NBC’s 50th anniversary special in 1976. In 1954, he starred in his own television series, The Donald O’Connor Show on NBC. In 1968, O’Connor hosted a syndicated talk show also called The Donald O’Connor Show.[6] He suffered a heart attack in 1971.

O’Connor overcame alcoholism after being hospitalized for three months after collapsing in 1978.[4] His career had a boost when he hosted the Academy Awards, which earned him two Primetime Emmy nominations. He appeared as a gaslight-era entertainer in the 1981 film Ragtime, notable for similar encore performances by James Cagney and Pat O’Brien. It was his first feature film role in 16 years. O’Connor appeared in the short-lived Bring Back Birdie on Broadway in 1981, and continued to make film and television appearances into the 1990s, including the Robin Williams film Toys as the president of a toy-making company. He had guest roles in 1996 in a pair of popular TV comedy series, The Nanny and Frasier. In 1998, he received a Golden Palm Star on the Palm Springs, California, Walk of Stars. O’Connor’s last feature film was the Jack Lemmon-Walter Matthau comedy Out to Sea, in which he played a dance host on a cruise ship. O’Connor was still making public appearances well into 2003. The most distinctive characteristic of O’Connor’s dancing style was its athleticism, for which he had few rivals. Yet it was his boyish charm that audiences found most engaging, and which remained an appealing aspect of his personality throughout his career. In his early Universal films, O’Connor closely mimicked the smart alec, fast talking personality of Mickey Rooney of rival MGM Studio. For Singin’ in the Rain, however, MGM cultivated a much more sympathetic sidekick persona, and that remained O’Connor’s signature image.

O’Connor was married twice and had four children. His first marriage was in 1944 to Gwendolyn Carter, with whom he had a daughter, Donna. The couple divorced in 1954. He married for a second time, to Gloria Noble, in 1956. Together they had three children; Alicia, Donald Frederick and Kevin. O’Connor and Noble remained married until his death in 2003. O’Connor had undergone quadruple heart bypass surgery in 1990, and he nearly died from double pneumonia in January 1998. He died from complications of heart failure on September 27, 2003 at age 78 at the Motion Picture & Television Country House and Hospital, in Woodland Hills, California. His remains were cremated and buried at the Forest Lawn–Hollywood Hills Cemetery in Los Angeles. O’Connor was survived by his wife, Gloria, and four children. Gloria O’Connor died from natural causes on June 4, 2013, aged 84.