Capirossi made his World Championship debut in the 125cc class in 1990 with the Polini Honda team, operated by former world champion Paolo Pileri. In his first full Grand Prix season he took wins in Britain, Hungary, and Australia and claimed the world title at the unprecedented age of seventeen years, five months, and thirteen days. He defended the championship the following year in equally dominant fashion: he was only once off the front row of the grid across thirteen rounds, recording five pole positions, four fastest laps, and finishing on the podium twelve times, with wins in Australia, Malaysia, and three European venues.
Capirossi moved to the 250cc class in 1992. He had near-miss championship battles in 1993, finishing second by four points behind Harada, and again in 1994 behind Max Biaggi and Tadayuki Okada. He briefly entered the 500cc class in 1995 and 1996 before returning to 250cc in 1997.
The 1998 season produced his third world title in contentious circumstances. Capirossi battled Aprilia teammate Tetsuya Harada down to the Argentine Grand Prix. In the final corner of the final lap, with Harada positioned to take second, Capirossi's machine made contact with Harada's, sending the Japanese rider off the track. Capirossi claimed second and, following an appeal, the world championship. Aprilia released him after the season.
He joined Honda for 1999, finishing third in the championship with three victories, though the season was not without controversy: at Mugello he was black-flagged for dangerous riding following an incident at the start.
Capirossi returned to the premier class in 2000 and remained through the transition from 500cc two-strokes to the 990cc and eventually 800cc four-stroke MotoGP era. He joined Ducati in 2003 and gave the Italian manufacturer its first Grand Prix win in years at Barcelona, finishing fourth in the championship. Gradually improving Bridgestone tyres helped him take two victories in Japan and Malaysia during 2005.
The 2006 season was among his strongest in MotoGP. He opened the year with a victory at Jerez and was temporarily tied for the championship lead with Nicky Hayden before a multi-bike collision at Barcelona interrupted his momentum. He recovered to take another dominant victory at Brno, pulling away from the entire field, and finished the year third in the championship. His nine premier-class race wins across a career spanning Honda, Suzuki, and Ducati made him one of only a handful of riders to win top-class races with three different manufacturers.
After leaving Ducati, Capirossi moved to Suzuki in 2008 and 2009, then joined the Pramac Ducati satellite team for his final season in 2011. On 11 April 2010, at the season-opening Qatar Grand Prix, he became the first rider in Grand Prix history to start 300 races. He announced his retirement on 1 September 2011.
Capirossi's race number 65 was retired from all classes of Grand Prix motorcycle racing in a ceremony during the 2016 Valencia Grand Prix weekend. Following his retirement, he became Safety Advisor to Dorna Sports, the commercial rights holder of Grand Prix motorcycle racing, bringing his on-track experience into the governance and safety structures of the sport. A biography, "65 – la mia vita senza paura" (65 – my life without fear), was published in Italy in 2017. He is also a member of the Champions for Peace club, a group of elite athletes committed to promoting peace through sport.