Fisichella made his Formula One debut with Minardi in 1996 before moving to Jordan in 1997, where he earned his first podium finishes at the Canadian and Belgian Grands Prix. He joined Benetton in 1998, claiming his first pole position at the Austrian Grand Prix. After a run of consistent but often unlucky performances, he won his first Formula One race for Jordan at the controversial 2003 Brazilian Grand Prix, which was declared after five days of deliberation due to a timekeeping error; he became the only Formula One driver to have won a race without standing atop the podium at the time, collecting his trophy at the subsequent Imola race.
His strongest Formula One period came at Renault, where he won the opening race of the 2005 season in Australia and won the Malaysian Grand Prix from pole in 2006, finishing fourth in the World Drivers' Championship that year and contributing to back-to-back Constructors' titles for Renault alongside Fernando Alonso. At Force India in 2009, Fisichella took the team's first pole position and first podium at the Belgian Grand Prix, leading to a mid-season call-up to Ferrari as a replacement for the injured Felipe Massa for the remainder of the 2009 season.
Fisichella made his sports car racing debut in 2010 driving for AF Corse in a Ferrari F430 in the Le Mans Series. In 2011, partnering Gianmaria Bruni and the AF Corse team, he won the LMGTE Pro class of both the Le Mans Series drivers' and teams' championships, adding a win at the 1000 km of Spa and contributing to the Intercontinental Le Mans Cup team title.
At the 80th edition of the 24 Hours of Le Mans in 2012, Fisichella, Bruni, and Toni Vilander drove their Ferrari 458 Italia to first place in the GTE-Pro class, completing 335 laps of the Circuit de la Sarthe. Fisichella drove the final stage of the race. He also won the season opener of the 2012 World Endurance Championship at the start of that year.
After a difficult 2013 that saw him race in the IMSA-predecessor Tudor United SportsCar Championship with Risi Competizione in America, Fisichella returned to AF Corse and teammates Bruni and Vilander for the 2014 24 Hours of Le Mans. They again won the GTE-Pro class, covering 339 laps — four more than their 2012 victory. He returned to American competition afterward, winning at Road America and Virginia International Raceway. From 2018 to 2022, Fisichella again campaigned in the FIA World Endurance Championship before transitioning to Italian GT3 competition.
Outside of driving, Fisichella founded FMS International, his eponymous GP2 team, in 2005. The team competed in the GP2 Series from 2006 to 2009, managing drivers through the feeder series.
Fisichella married Luna Castellani on 10 October 2009. They have three children: Carlotta, Christopher, and Carolina. He is a supporter of Roma in Serie A and captains the official Nazionale Piloti association football team for racing drivers. Fisichella is related to the Fisichella family of Sicilian nobility. He has a cameo appearance in the 2019 film The Art of Racing in the Rain as a Ferrari crew member.