Born in Rome, Fisichella began karting as a youngster and moved to Italian Formula Three in 1992 with the RC Motorsport team. He finished runner-up in 1993 before winning the championship in 1994, also claiming victory at the prestigious Monaco Formula Three Grand Prix. A season in the Deutsche Tourenwagen Meisterschaft with Alfa Romeo followed in 1995-96 before he graduated to Formula One.
Fisichella debuted with Minardi in 1996 as official test driver the previous season, though Minardi later replaced him mid-season with a driver who could bring funding. He moved to Jordan in 1997, partnering Ralf Schumacher. He took his first podium at the Canadian Grand Prix and nearly won at Hockenheim before a puncture intervened. A strong second place in the rain-soaked Belgian Grand Prix impressed the Benetton team enough to sign him for 1998.
At Benetton, Fisichella established himself as a consistent points scorer and podium finisher despite the team's declining competitiveness after Renault's engine withdrawal. He claimed his first pole position at the 1998 Austrian Grand Prix. Highlight results included multiple second-place finishes at Montreal and Monaco in 1998 and 1999. He consistently outperformed teammates Jean Alesi, Alexander Wurz, and Jenson Button, including a late-season third at the 2001 Belgian Grand Prix, yet was not retained when Renault purchased the team.
Returning to Jordan for 2002, Fisichella again outpaced his teammate, this time Takuma Sato. In 2003, despite Jordan's switch from Honda to Ford engines and continued lack of competitiveness, he delivered the team's signature result at the Brazilian Grand Prix. Racing through heavy rain and multiple crashes, he overtook Kimi Raikkonen to take the lead on lap 54 before the race was red-flagged. He was initially classified second under the regulations, which determined results at two laps before the red flag — at which point Raikkonen was thought to have been leading. After several days of deliberation and FIA investigation, officials determined Fisichella had already begun his 56th lap before the red flag, awarding him the victory. He became the only Formula One driver to have won a race without initially standing atop the podium, collecting his winner's trophy at the following round at Imola.
Fisichella moved to Sauber for 2004 and drove strongly throughout the season, outpacing teammate Felipe Massa for much of it and scoring 22 points to Massa's 12.
Reunited with former team boss Flavio Briatore at Renault, Fisichella opened the 2005 season with a dominant win from pole at Melbourne. Despite the strong start, Fernando Alonso's superior consistency throughout the year kept Fisichella behind in the championship standings; a notable low point came in Japan when he lost the race lead on the final lap to Raikkonen despite team radio instructions to protect the position. Renault won the World Constructors' Championship regardless.
In 2006, Fisichella won in Malaysia from pole and contributed to Renault securing back-to-back Constructors' titles. He achieved his best World Drivers' Championship result — fourth — with 72 points and five podiums. His 2007 season as Renault's lead driver after Alonso's departure was more difficult; the car lacked the pace of previous seasons and he was unable to fight for wins.
Fisichella joined Force India for 2008 and 2009. The 2008 season was fruitless, but at the 2009 Belgian Grand Prix he produced the result of his later career: qualifying on pole and finishing second, earning Force India their first points and first podium in Formula One history. The performance prompted Ferrari to sign him to replace the injured Felipe Massa for the remaining five races of the season, fulfilling a long-held ambition. He remained Ferrari's reserve driver through 2010 before his role was taken over by Jules Bianchi.
From 2010 Fisichella raced sportscars with AF Corse in Ferraris across the Le Mans Series and FIA World Endurance Championship. In 2011 he and teammates Gianmaria Bruni won the LMGTE Pro class of both the Le Mans Series drivers' and teams' championships. In 2012 Fisichella, Bruni, and Toni Vilander won the 24 Hours of Le Mans GTE Pro class, their Ferrari 458 Italia completing 335 laps. That same year, they won the WEC GTE Pro drivers' and teams' championships. He won at Le Mans again in 2014 in what the team described as a hard-fought race, completing 339 laps — four more than their 2012 total.
Fisichella founded Fisichella Motor Sport (FMS International) in 2005, managing a GP2 team from 2006 to 2009. He is a passionate supporter of Roma in Serie A and captains the Nazionale Piloti, a football team of racing drivers.