Antonovich was born in Los Angeles, California, and attended Thomas Alva Edison Junior High, where one of his classmates was Henry Waxman. He graduated from John Marshall High School and enlisted in the United States Army Reserve in 1957. A member of Sigma Nu fraternity, Antonovich graduated from California State University, Los Angeles in 1963 with a bachelor's degree and a Master's degree in 1966. Antonovich taught in the Los Angeles Unified School District and later at Pepperdine University.
In 1969, Antonovich was elected to the newly formed Los Angeles Community College District Board of Trustees.
In 1972, he was elected to the California State Assembly and for three terms represented Glendale, Burbank, Sunland, Tujunga, Atwater, Griffith Park, Lakeview Terrace and Sun Valley. He served as a Republican Whip in the Assembly from 1976 to 1978.
Antonovich ran unsuccessfully for the Republican nomination for Lieutenant Governor of California in 1978 against Mike Curb. After Curb defeated him in the primary and in the general election, he declined to specifically endorse Curb, but instead endorsed the entire Republican ticket. Curb defeated incumbent Mervyn Dymally in the general election. In 1984 Antonovich was elected chairman of the California Republican Party and served for two years.
He served as Chairman of the Board of Supervisors (to which he was first elected in 1980) in 1983, 1987 and 1991 and as the so-called "Mayor of Los Angeles County" in 1983, 1987, 1991, 2001 and 2006.
He ran for the U.S. Senate in 1986 in a three-way primary. Antonovich received the endorsement of television evangelist Pat Robertson. He and Bruce Herschensohn were unsuccessful, and Ed Zschau went on to lose to the incumbent, Alan Cranston. Antonovich lost the San Fernando Valley to Herschensohn.
In 2016, Antonovich ran for California State Senator for the 25th District, which includes the cities of Burbank, Glendale, Pasadena, La Canada Flintridge, South Pasadena, Monrovia, Bradbury, Duarte, Glendora, San Dimas, La Verne, Claremont, Upland, Sierra Madre, the unincorporated communities of Altadena, East Pasadena, and La Crescenta-Montrose, and the Los Angeles neighborhoods of Atwater Village and Sunland-Tujunga.
On November 8, 2016, Antonovich lost the California State Senate election for the 25th District to Democrat Anthony Portantino by a 57 percent to 43 percent.
He was re-elected to the Board of Supervisors in 2012 served until 2016, when term limits forced him to leave office.
From 2007 to 2013, Antonovich received $1,862,796.59 in campaign contributions, reported by Los Angeles Registrar-Recorder/County Clerk records. 
Michael D. Antonovich Trail near San Dimas, California, and Michael D. Antonovich Regional Park at Joughin Ranch in the Santa Susana Mountains are named after him.
Antonovich objected to the appointment of Duke University professor Erwin Chemerinsky to be dean of the new law school at the University of California, Irvine, and lobbied against it. The university rescinded the appointment, then later restored it.
Antonovich is of Croatian descent.
On February 15, 1998, he married Christine Hu Huiling, a Mandarin-speaking actress from Dalian, China, before 900 guests; Red Buttons and Pat Boone were lay lectors. Hu has two children with Antonovich: a son, Michael Jr., born in 1999, and a daughter, Mary Christine, born in 2000.