Bono was born Mary Whitaker in Cleveland, Ohio, the daughter of Karen Lee (née Taylor), a Chemist, and Dr. Clay Westerfield Whitaker, a physician and World War II veteran. In 1963, in her second year, she moved with her parents to South Pasadena, California.

She graduated from the University of Southern California in 1984 with a bachelor of arts in art history. She was an accomplished Gymnast in her youth.

In 1986, she married actor/singer Sonny Bono and moved to Palm Springs where the two operated a restaurant they owned. Sonny Bono served as Mayor of Palm Springs from 1988 to 1992 before being elected to Congress in 1994. During her marriage to Sonny Bono, Mary took courses in Scientology but never took to the religion. After Bono's death, she began dating Brian Prout, Drummer of the country music band Diamond Rio. The two became engaged in 2001 but did not marry.

Mary Bono has a son born in 1988, and a daughter born in 1991, from her marriage to Sonny Bono. In addition to her family, Bono has interests in music and outdoor activities such as hiking and camping. In the April 2008 edition of Golf for Women magazine, she was listed as "one of the 50 most powerful women who play" golf.

She was named one of the "Most Fascinating Women of 1998" by Ladies' Home Journal magazine in conjunction with CBS Television. She was also selected by the former George magazine as one of the 20 most fascinating women in politics. In 2008, she was named the "Seventh Hottest Politician in the World" by Maxim.

Mary Bono served in Congress for 15 years, where she worked on legislation and issues related to intellectual property, Energy, health, telecommunications, privacy and more. Her legislative work includes a bill that calls for country-of-origin labeling for fresh fruits and vegetables, as well as several energy-saving bills to reward companies for utilizing clean burning fuel technologies and increase the energy-efficiency of federal buildings. In 2000, Bono helped pass legislation that established the Santa Rosa and San Jacinto Mountains National Monument in the Palm Springs region. The House of Representatives passed her Securely Protect Yourself Against Cyber Trespass (SPY ACT), which would protect an individual's personal information on the Web. Bono secured federal recognition of Frank Sinatra Day, which was to be every subsequent May 13. Also, Bono has sponsored legislation that provides funding for obesity studies and improved nutrition programs nationwide, autism research, and Federal funding under the Ryan White HIV/AIDS Act. In 2011, her bill, H.R. 2715, was signed into law with bipartisan support to amend and improve the Consumer Product Safety Improvement Act of 2008. The daughter of a veteran, Bono also played a key role in creation of much-needed VA clinics in Blythe and Palm Desert, California.

Bono followed the Republican Party line 89% of the time, according to Congressional Quarterly. In 2004, she received an 84% approval rating from the Christian Coalition of America, but this fell to 33% in 2008. In 1999, she voted in favor of the Largent Amendment, to ban adoption by same-sex couples in Washington, D.C. Bono has, however, voted against the Federal Marriage Amendment twice. In June 2009, she voted for the American Clean Energy and Security Act, which would have implemented a national cap and trade system for greenhouse gas emissions. In December 2010, she was one of fifteen Republican House members to vote in favor of repealing the United States military's "Don't Ask, Don't Tell" ban on openly homosexual Service members. In 2013, after losing reelection, Bono was a signatory to an amicus curiae brief submitted to the Supreme Court in support of same-sex marriage during the Hollingsworth v. Perry case.

In 2001, she married Wyoming businessman Glenn Baxley about 18 months after they met in Mexico. They filed for divorce in 2005. On December 15, 2007, Bono married Congressman Connie Mack IV (R-FL) in Asheville, North Carolina. In May 2013, the couple announced they had separated on amicable terms and divorced later that month.

After the 2010 census, however, her district was renumbered as the 36th District and made somewhat more Democratic. In a significant upset, Democratic challenger Raul Ruiz, a physician, defeated her with 53 percent of the vote to Bono Mack's 47.1 percent.

Bono was chairwoman of the House Energy Subcommittee on Commerce, Manufacturing and Trade. This committee debates legislation related to intellectual property, telecommunications, Energy and Health care. She was the first Republican woman to chair this subcommittee. She was co-chair of the Congressional Caucus on Prescription Drug Abuse. In 2012, she formed and chaired the House Women's Policy Committee, which included 24 female Republican lawmakers from 17 states.

In August 2013, Bono was a panelist at the National Journal's Women 2020 event and discussed her experiences as a woman in Congress and work that still needs to be done regarding gender equality.

In September 2015, Bono married former Astronaut and retired Navy rear admiral Stephen S. Oswald.