Born in San Jose, California, Mamola initially pursued a career as a musician before his interests shifted to motorcycle racing at age 12. He idolized fellow Northern Californian racer Kenny Roberts. Mamola began competing in dirt track racing and earned sponsorship from Yamaha at 14. He then focused on road racing with coaching from former racer Ron Grant.
In 1977, Mamola gained international exposure competing in the New Zealand Marlboro Series. He also began competing professionally in the AMA 250cc road racing championship, finishing as runner-up. In 1978, he won the AMA 250cc road racing title and earned the nickname "Baby Kenny." His performance secured him a place on the American team for the 1979 Transatlantic Trophy match races, where he finished as the second highest points scorer behind Mike Baldwin and ahead of Barry Sheene.
Mamola entered the 1979 250cc Grand Prix road racing world championships on a Yamaha powered Bimota race bike. After a difference of opinion with his sponsors, he switched to a Yamaha TZ-250 sponsored by Serge Zago. When Zago's 500cc rider, Mike Baldwin, was injured, Mamola moved to the premier class, taking over the team's Suzuki RG 500. He scored a second place at the Finnish Grand Prix and led the French Grand Prix for five laps, finishing second ahead of Kenny Roberts. He ended his rookie season ranked fourth in the 250cc class and eighth in the 500cc class.
Mamola's rookie season earned him a full sponsorship from the Suzuki factory racing team for the 1980 season. He won his first 500cc Grand Prix race at the 1980 Belgian Grand Prix, becoming the youngest Grand Prix premier class winner at 20 years, 239 days. This record surpassed Mike Hailwood's 1961 record and was later broken by Freddie Spencer in 1982. Mamola won again at the British Grand Prix and finished second in the final standings behind Kenny Roberts. He concluded the 1980 season with a victory at the Mallory Park Race of the Year.
In 1981, Mamola started strongly with two victories and two second-place finishes, taking the championship lead. However, Gallina-Suzuki rider Marco Lucchinelli claimed the 1981 500cc world championship. Mamola's crew chief, Jeremy Burgess, believed Mamola would have won with Michelin tires instead of Dunlop tires. Mamola finished second for the second consecutive year.
After a challenging start to the 1982 season, Mamola recovered to score two second places and a victory in the last three races, finishing sixth in the standings. The 1983 season was dominated by Honda's Freddie Spencer and Yamaha's Kenny Roberts. Mamola rode the aging Suzuki RG 500 to a respectable third place in the championship standings.
When Suzuki withdrew from Grand Prix racing after the 1983 season, Mamola lost his job. However, Honda contracted him to join their racing team after Freddie Spencer suffered an injury. Mamola rode the Honda NS 500 to a second-place finish behind Eddie Lawson at the 1984 Spanish Grand Prix. He won three of the last five races, including the British Grand Prix at Silverstone aboard the new V4 Honda NSR500. Despite a late-season surge, Mamola finished second in the championship behind Eddie Lawson, marking his third time as runner-up in the 500cc world championship.
In 1985, Mamola had a disappointing season, though he won the Dutch TT. He also performed a miraculous save at the San Marino Grand Prix after his rear tire lost and regained traction, allowing him to regain control of his motorcycle.
Mamola joined the newly formed Kenny Roberts-Yamaha team in 1986. Riding a YZR-500, he won the Belgian Grand Prix and scored six podium results, finishing third behind Eddie Lawson and Wayne Gardner. At the French Grand Prix, Mamola performed a stoppie just before the finish line, an act that displeased Kenny Roberts. Mamola began the 1987 season with a victory at the Japanese Grand Prix. He scored two more victories at the French and San Marino Grands Prix, as well as nine podium results, finishing second behind Wayne Gardner. Kenny Roberts replaced Mamola for the 1988 season with Wayne Rainey and Kevin Magee.
Mamola then joined Cagiva to help develop their Cagiva C589 race bike, staying for three years. After sitting out the 1991 season, he returned in 1992 for one last year on a privately supported Yamaha. He scored his final podium finish with a third place at the 1992 500cc Hungarian Grand Prix and finished the season ranked 10th.
Mamola won a total of 13 Grands Prix and finished second in the championship four times: in 1980, 1981, 1984, and 1987. During his Grand Prix career, he rode for Yamaha, Suzuki, Honda, and Cagiva.
After retiring from competition, Mamola remained involved in motorcycle racing as a test rider for Yamaha. He later became a television commentator for motorcycle Grand Prix races and a columnist for motorcycle magazines.
Mamola began his charity work in 1986 with Save the Children. This led him to co-found Riders for Health, an organization providing vehicles for healthcare delivery in Africa. More recently, he has been involved with Two Wheels for Life. Mamola is a figurehead for the charity at motorsports events, raising money through donations and offering fast laps on a two-seater Ducati MotoGP bike.
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