A multiple karting champion, de Cesaris graduated to Formula 3 in Britain and finished second in the 1979 British Formula Three Championship, runner-up to Chico Serra. He then moved to Formula 2 with Ron Dennis's Project 4 team, which would later merge with McLaren.
Alfa Romeo signed de Cesaris for the final two races of 1980. His debut in Canada ended with engine failure after eight laps; at Watkins Glen he crashed into the catch fencing after tangling with Derek Daly on lap two.
In 1981, his Marlboro personal sponsorship — which matched McLaren's main backer — secured him a seat at McLaren, the team having been rebuilt under Ron Dennis after merging with Project 4. De Cesaris was fast at times, particularly on high-speed circuits, but he crashed 19 times during the season in practice or races. The team withdrew his car from the Dutch Grand Prix at Zandvoort rather than risk him crashing it. He finished only six of his 14 starts. The nickname "Andrea de Crasheris" followed him for years, and Dennis was so frustrated that he never hired another Italian driver to McLaren.
Back at Alfa Romeo in 1982, de Cesaris became the youngest driver ever to take pole position at Long Beach. He led the race but waved his fist at a backmarker at a critical moment, missed a gear change, hit the rev limiter, and Niki Lauda passed him to win. At Monaco that year, he ran out of fuel on the final lap while in a strong position, allowing Riccardo Patrese to take victory.
The 1983 season, with a turbocharged Alfa Romeo, brought his best results. He twice finished second — at the German Grand Prix at Hockenheim and at the South African Grand Prix at Kyalami. He was also on course for a likely win at Spa-Francorchamps, comfortably leading Alain Prost's Renault for much of the race before a botched pit stop and eventual engine failure ended his challenge. He finished the season ninth in the standings, his best championship result since 1982.
At Ligier from 1984, the Renault turbo engine was promising but results were modest. In 1985, de Cesaris was fired by Guy Ligier after a quadruple mid-air rollover at the Austrian Grand Prix destroyed his car. He moved to Minardi in 1986, going the entire season without a point. At Brabham in 1987, driving a BMW-powered car, he took a third place at Spa — his first podium since 1983 — though he failed to finish 14 of 16 races. The following year with the new Rial team and a Cosworth engine, he qualified for all sixteen races and took a fourth place at Detroit.
With the Marlboro-backed Dallara team in 1989, de Cesaris was in contention for a Monaco podium before being taken out by Nelson Piquet. In Canada, after an early delay, he finished third in a rain-soaked race behind two Williams cars — the last time he would stand on a Formula One podium.
In 1991, Eddie Jordan signed him for Jordan's debut Formula One season. At the Belgian Grand Prix at Spa, de Cesaris moved through the field into second position before his Ford V8 blew — a result complicated by a communication error between Ford and Jordan over oil tank capacity for a new piston ring design. He finished the season ninth in the championship.
After two seasons at Tyrrell (1992–1993), de Cesaris made a brief return in 1994 with Jordan, covering for the suspended Eddie Irvine, then signed by Sauber when that team needed a replacement for the injured Karl Wendlinger. His 200th Grand Prix start came at Canada with Sauber. His Formula One career ended at the 1994 European Grand Prix with a throttle problem.
De Cesaris scored points for nine of the ten teams he raced for — McLaren, Alfa Romeo, Brabham, Rial, Tyrrell, Jordan, Ligier, Scuderia Italia, and Sauber — failing to score only with Minardi. He also holds the records for the most consecutive non-finishes in a career (18, spanning 1985–1986) and the most DNFs in a single season (14 in a 16-race year, 1987). After retirement he became a successful currency broker in Monte Carlo. He participated in the Grand Prix Masters series for retired Formula One drivers in 2005 and 2006. On 5 October 2014, de Cesaris was killed when he lost control of his motorcycle on Rome's Grande Raccordo Anulare motorway. He was 55.