After graduating from Brown University in 1930, Kerner attended Trinity College at Cambridge University in England from 1930 to 1931. In 1934 he received a law degree from Northwestern University in Chicago and was admitted to the Illinois bar. On 20 October 1934, he married Helena Cermak, daughter of the late Anton Cermak, who had been mayor of Chicago before he was shot and mortally wounded in Miami, Florida in 1933 by Giuseppe Zangara in what may have been an attempt on the life of president-elect Franklin D. Roosevelt.
Kerner joined the 33rd Division of the Illinois National Guard in 1934. In 1942, he entered active duty in World War II, serving as a field artillery officer in the 9th Infantry Division of the United States Army in North Africa and Italy and in 32nd Infantry Division in the Pacific. He was awarded the Bronze Star Medal for merit and the Soldier's Medal for rescuing a drowning soldier off the coast of Sicily. He was released from active duty in 1946 as a Lieutenant Colonel and rejoined the Illinois National Guard. In the 33rd Division, Kerner was promoted to the rank of Colonel that same year and to Brigadier General in 1951. He retired in 1954 as a Major General.
He defeated incumbent Governor William G. Stratton in the 1960 election and was re-elected in 1964, defeating moderate Republican Charles H. Percy, who was later elected to the U.S. Senate. As governor, Kerner promoted economic development, education, mental health services, and equal access to jobs and housing. He served on the National Governors' Conference Executive Committee from 1967 to 1968, and he chaired the Midwestern Governors' Conference that same year. In July 1967, President Lyndon B. Johnson appointed the National Advisory Commission on Civil Disorders and named Kerner its chairman.
Kerner resigned as governor on May 20, 1968 to become a judge on the United States Court of Appeals for the Seventh Circuit.
Kerner retained famed attorney Neil Papiano to represent him. Following a 1973 trial in which his prosecutor was future Illinois governor James R. Thompson, Kerner was convicted on 17 counts of bribery, conspiracy, perjury, and related charges. He was sentenced to three years in federal prison and fined $50,000. Faced with almost certain impeachment, he resigned his position on the federal bench on July 22, 1974. During the early 1970s a Chicago disc jockey began doing segments known as "Blotto Otto" in which a Kerner impersonator would call pretending to be the inebriated governor. The station pulled the segment after four weeks because they felt it was in poor taste. Kerner was released from prison early when it was determined that he was suffering from terminal cancer.