Born in Milwaukee on January 21, 1926, he graduated from the University of Chicago Law School in 1951. After clerking for Supreme Court Justice Sherman Minton, he spent ten years in the Illinois state legislature before serving in the U.S. Congress from 1969-73 and 1975-79, when he resigned to accept an appointment to the United States Court of Appeals for the District of Columbia Circuit. His status as an independent Democrat hostile to the Chicago Democratic machine enhanced his electability in a predominantly Republican suburban district. He first represented the South Shore district of Chicago along the lake front wards and Hyde Park, home to the University of Chicago. Both parties attempted to redistrict Mikva out of Congress. He then moved to the North Shore and successfully ran as an Independent Democrat. In 1978 he had been narrowly reelected against Republican John Porter in what was one of the most expensive congressional races to that time. (Mikva then resigned the seat in 1979, and Porter succeeded him anyway after another special election.)

He taught law at Northwestern University and was White House Counsel from 1994-95.

In November 2004, Mikva was an international election monitor of Ukraine's contested presidential election.

He returned to the University of Chicago Law School, serving as the Schwarz Lecturer and the senior director of the Mandel Legal Aid Clinic.