Originally from the Gold Coast, Queensland, Doohan attended St Joseph's College, Gregory Terrace and Aspley State High School in Brisbane. He raced in Australian Superbikes in the late 1980s, winning both races when the Superbike World Championship visited Oran Park in 1988, as well as the second leg of the Japanese round that year. He also won the final Australian motorcycle Grand Prix held in the TT format at Mount Panorama before the race joined the World Championship and moved to Phillip Island.
Doohan made his Grand Prix debut for Honda on the NSR500 two-stroke in 1989. Late in 1990 he claimed his first victory at the Hungarian Grand Prix, finishing third in that season's championship. In 1991 he was paired with fellow Australian Wayne Gardner on a Honda RVF750 and won the Suzuka 8 Hours endurance race.
Doohan's trajectory toward a first world title appeared clear when he built a 65-point championship lead heading into the 1992 Dutch TT at Assen. During a practice session he crashed and suffered severe damage to his right leg, including complications that at one stage led doctors to consider amputation. Unable to race for eight weeks, he returned for the final two rounds but could not prevent Yamaha's Wayne Rainey from winning the championship by four points.
The injury left permanent effects on his right leg and required a fundamental change to his riding technique. Because his right foot could no longer operate the rear brake effectively, Doohan developed a thumb-operated rear brake mounted on the left handlebar — a "nudge" bar similar to a personal watercraft throttle. He spent 1993 managing the physical limitations while retaining his Honda factory ride, later describing that year as simply trying to keep his seat.
From 1994, Doohan was unstoppable. He won the 500cc World Championship that year and then defended it through 1995, 1996, 1997, and 1998 — five consecutive titles. His 1997 campaign was his most dominant: he won 12 of 15 races, finished second in two more, and was leading at his home Australian Grand Prix when he crashed out of the final round. His margin over the field was often such that he would build a comfortable lead and then ride conservatively to the flag.
A key factor in his sustained dominance was the technical partnership with chief race engineer Jeremy Burgess, who refined the Honda NSR500's suspension and geometry to suit Doohan's requirements. The bike's setup remained largely stable between 1994 and 1998, with Honda engineers reportedly frustrated by Doohan's reluctance to experiment with innovations such as electronic shifting — changes that were only adopted when Valentino Rossi joined Honda after Doohan's retirement.
In 1999, during a wet qualifying session for the Spanish Grand Prix, Doohan crashed again and broke his leg in multiple places. He subsequently announced his retirement from racing. He had accumulated eight rivals on non-factory Honda machinery during the championship years, yet his margins of victory regularly reflected a level of superiority beyond what the hardware alone could explain.
After retirement, Doohan worked as a roving adviser to Honda's Grand Prix program until parting company with them at the end of 2004. He tested a Williams FW19 Formula One car at Circuit de Catalunya in April 1998 and found it difficult to drive, crashing against a barrier. In 2001 he drove a Mercedes-Benz CLK55 AMG in the Targa Tasmania rally. In June 2011 he completed a parade lap at the Isle of Man TT, where he paid tribute to former Honda teammate Joey Dunlop.
Doohan collaborated on the design of an Intamin motorcycle launch roller coaster, Mick Doohan's Motocoaster, at Dreamworld on the Gold Coast. His branding was removed from the ride in May 2022. His son Jack Doohan became a Formula One racing driver.
Doohan was appointed a Member of the Order of Australia in the 1996 Queen's Birthday Honours. He received an Australian Sports Medal in 2000 and was inducted into the Sport Australia Hall of Fame in 2009. He was named one of the Q150 Icons of Queensland in 2009. The first turn at the Phillip Island Grand Prix Circuit bears his name. The City of Gold Coast presented him with the Key to the City in 1997.
Doohan's five consecutive 500cc titles place him second in the all-time list for premier-class world championships, behind only Valentino Rossi. His adaptation to racing with a permanently injured leg — redesigning his braking system rather than retiring — is among the most discussed examples of technical problem-solving in motorcycle sport. Jeremy Burgess, who engineered all five of his championships, went directly to work with Rossi, underlining the human continuity that underpinned both dynasties.