Born in Locorotondo, Bari, Liuzzi began kart racing at the age of nine. He won the 1993 Italian Karting Championship and took second at the 1995 World Championship before claiming the title outright in 2001, defeating Formula One champion Michael Schumacher at Kerpen, Schumacher's home track, in the process.
After moving to cars, Liuzzi finished second in the 2001 German Formula Renault Championship. He joined the Red Bull Junior Team for the 2002 German Formula Three Championship, finishing ninth, and tested for Coloni's Formula 3000 squad and Williams the same year. He spent the 2003 F3000 season with Red Bull before switching to Arden for 2004, where he dominated the field, winning seven of the ten rounds and securing the championship with one round to spare.
Red Bull signed Liuzzi for the 2005 Formula One season but ultimately gave the race seat alongside David Coulthard to Christian Klien, with Liuzzi starting as test driver. Under a pre-season agreement both drivers were to be given races, and Liuzzi replaced Klien for the San Marino, Spanish, Monaco, and European Grands Prix. He scored his first championship point on debut at San Marino, benefiting from the post-race disqualification of both BAR cars. He was returned to a test role after the European Grand Prix.
When Red Bull purchased the Minardi team and renamed it Scuderia Toro Rosso, Liuzzi was rewarded with a full-season race seat. At the 2006 United States Grand Prix he scored the team's first championship point with an eighth-place finish after a race-long battle with David Coulthard and Nico Rosberg; it was the team's sole point for the season.
Liuzzi returned for 2007 but the first half of the season was plagued by mistakes. He appeared set to score at Canada before crashing into the Wall of Champions at the final chicane. His form improved in the second half once Sebastien Bourdais was confirmed as his 2008 replacement, culminating in arguably his finest Formula One drive in China. Starting eleventh, he gained three places at the start and then overtook Mark Webber and Nick Heidfeld, ultimately holding off Heidfeld's late charge to finish sixth and claim three points.
Without a Toro Rosso seat, Liuzzi signed as test driver for Force India in January 2008, with the prospect of a race seat once the contracts of Adrian Sutil and Giancarlo Fisichella expired. When Ferrari released Fisichella to replace the injured Felipe Massa, Force India announced Liuzzi would take over Fisichella's seat for the final five rounds of 2009. He debuted for the team at the Italian Grand Prix from seventh on the grid before retiring with a transmission problem after 22 laps.
Force India retained both Sutil and Liuzzi for 2010, which proved Liuzzi's most successful Formula One season. He scored points at Bahrain, Australia, Monaco, Belgian, and Korean Grands Prix, finishing 15th in the championship with a career-best 21 points. His best result was two sixth-place finishes — at the Canadian Grand Prix (where he qualified a career-best sixth) and at Korea. Despite holding a valid contract for 2011, he was replaced by Paul di Resta.
Liuzzi was linked with a replacement role at Lotus Renault GP following Robert Kubica's rally accident in early 2011, but the team chose Nick Heidfeld. He instead joined Hispania Racing (HRT), where he and teammate Narain Karthikeyan spent the season at the back of the field. He failed to qualify for the Australian Grand Prix and thereafter primarily finished as the last classified runner on multiple occasions before losing his seat to Karthikeyan for the Indian Grand Prix; he returned for Abu Dhabi and Brazil, retiring from the latter on lap 61 with alternator failure. He did not secure a 2012 race seat despite holding a contractual option.
After Formula One, Liuzzi competed in the International Superstars Series in 2012, winning on his first day of competition at Monza in a Mercedes C63 AMG for CAAL Racing. In 2014 he moved to Japan, competing in the Super GT GT500 class for the Autobacs Racing Team Aguri (ARTA) alongside Kosuke Matsuura, and also contested the Super Formula series. He later appeared in Formula E.
In 2013 Liuzzi and former F1 driver Johnny Herbert co-mentored six Gran Turismo players in a primetime ITV4 reality series that culminated in the contestants racing in the Dubai 24 Hour race as real drivers.