Domínguez first began racing in 1987 driving go-karts. He won three go-karting championships and represented Mexico in the World Karting Championships in Spain (1989), Italy (1990) and France (1991). He then raced in numerous developmental series in Mexico, eventually winning the Mexican Formula Three Championship in 1998 and moving to the American Indy Lights series full-time in 1999, finishing 8th in the championship in 2000 and 4th in the series’ final year, 2001. He was slated to make his Champ Car debut in the first race of the 2001 season in his home county’s race in Monterrey for the new Millennium Motorsports team, but the car never appeared.

Domínguez made his Champ Car debut the following year in 2002 and became Rookie of the Year, with his first Champ Car victory in 2002 at the Honda Indy 300, although this was in a rain-shortened race largely dictated by the safety car. He was more competitive in 2003, winning the Grand Prix Americas in Miami. In 2004 Domínguez had his best season to date by finishing 5th in the final standings. This success with Herdez Competition allowed him to sign with the Forsythe team for 2005. However, Domínguez saw limited success at Forsythe. After the first four races of the 2006 season where he crashed into his teammate Paul Tracy on the first lap twice, Domínguez and Forsythe parted ways. Before the next Champ Car race in Portland, Domínguez signed on to Dale Coyne Racing to drive the Sonny’s BBQ Ford Lola-Cosworth. For the final 3 races of the season, Domínguez secured sponsorship from Mexican state-owned petroleum company Pemex to race for the slightly more competitive Rocketsports team. Along with Champ Car racing, Mario tested a Jordan Grand Prix Formula One racing car at the Silverstone circuit in Northamptonshire, England, in 2005.

In 2007 he signed with Forsythe for the first three races of the season after obtaining sponsorship from Telmex, but was dropped after just a few rounds in favour of Oriol Servià. He remained out of a Champ Car ride until he replaced an injured Tristan Gommendy at PKV Racing at the Rexall Grand Prix of Edmonton. The following week at the San Jose Grand Prix, he signed on with Pacific Coast Motorsports to fill in for Ryan Dalziel, who was injured in a bicycling accident. Dalziel recovered enough to return to racing two weeks later at Generac Grand Prix at Road America, returning Mario to the sidelines. But at the Belgian Grand Prix at Zolder, Mario was again called on as a substitute after Dan Clarke of Minardi Team USA was suspended for the weekend after causing a multi-car crash in a practice session.

In 2008, Dominguez announced that he would enter the remainder of the 2008 IndyCar Series season with Pacific Coast Motorsports, after placing third in the final Champ Car race at Long Beach. He was bumped from the field at the 2008 Indianapolis 500 and made his first true start in the series in the following race at the Milwaukee Mile. Since his 21st-place finish at Texas Motor Speedway in June, Dominguez’s team skipped the next events to re-evaluate their program to be more competitive when they return. They returned on a road course only schedule and participated in the Watkins Glen, Mid-Ohio, Edmonton, and Infineon races to close out the season. His best finish of the season came at Watkins Glen in 13th place. He finished 27th in points.

In 2009, Mario has been offered a drive for the K Plus K Motorsport without the need to bring sponsorship. This will not be his first sportscar events, since he did a couple for a Risi Competizione American Le Mans Series team in 2006, delivering good results.