From 1956 to 1979, the top open wheel racing series in North America was the USAC National Championship. It was often referred to as Champ car racing, or Indycar racing, referring to the famous Indianapolis 500 race which was the centerpiece of the championship. The races were run on a mixture of paved and dirt ovals, and in later years also included some road courses.
Andretti made his Champ Car debut on April 19, 1964 at the New Jersey State fairgrounds in Trenton, New Jersey. He started sixteenth and finishing eleventh. Andretti was introduced by his USAC sprint car owner, Rufus Gray, to veteran mechanic Clint Brawner. Brawner was not impressed since sprint car drivers Stan Bowman and Donnie Davis had recently died, and Brawner's current driver, Chuck Hulse, had been critically injured. Chris Economaki recommended Andretti to Brawner, so Brawner watched Andretti race at Terre Haute, Indiana. Brawner was convinced that he had found the new driver for his team. The two stayed together for six years. Andretti finished eleventh in the USAC National Championship that season. Andretti won his first championship car race at the Hoosier Grand Prix on a road course at Indianapolis Raceway Park in 1965. His third place finish at the 1965 Indianapolis 500 in the Brawner Hawk earned him the race's Rookie of the Year award, and contributed towards Andretti winning the series championship. He was the youngest national champion in series history at age 25. He repeated as series champion in 1966, winning eight of fifteen events. He also won the pole at the 1966 Indianapolis 500. Andretti finished second in the IndyCars in 1967 and 1968. He also won a single non-championship drag race in 1967 in a Ford Mustang. In both 1967 and 1968, Andretti lost the season USAC championship to A.J. Foyt and Bobby Unser, respectively, in the waning laps of the last race of the season at Riverside, California, each by the smallest points margin in history.
Andretti won nine races in 1969, the 1969 Indianapolis 500, and the season championship. He also won the Pikes Peak International Hill Climb, which was part of the USAC National Championship. He was named ABC's Wide World of Sports Athlete of the Year. Between 1966 and 1969 he won 29 of 85 USAC championship races.
In 1973, USAC split its National Championship into dirt and pavement championships. Andretti had one win on the pavement and finished fifth in the season points, and finished second in the dirt championship. He competed in USAC's dirt track division in 1974, and won the dirt track championship while competing in both series. Andretti also competed in the North American Formula 5000 series in 1973 and 1974, and finished second in the championship in both seasons.
Andretti had continued to race, and occasionally win, in the USAC National Championship during his time in the Formula One world championship. In 1979 a new organization, Championship Auto Racing Teams, had set up the Indycar world series as a rival to the USAC National Championships that Andretti had won three times in the 1960s. The new series had rapidly become the top open wheel racing series in North America.
It was to this arena that Andretti returned full-time in 1982, driving for Patrick Racing. He returned to the 1982 Indianapolis 500 as well. After starting in row 2, Andretti got victimized by a controversial wreck during the pace-laps, when rookie Kevin Cogan suddenly spun out for no apparent reason. Andretti was livid and engaged in a shoving match with Cogan. In an interview 3 minutes after the wreck Andretti was heard saying "This is what happens when you have children doing a man's job up front."
In 1983 he joined the new Newman/Haas Racing team, set up by Carl Haas and actor Paul Newman using cars built by British company Lola. Andretti took the team's first win at Elkhart Lake in 1983. He won the pole for nine of sixteen events in 1984, and claimed his fourth Champ Car title at the age of 44. He edged out Tom Sneva by 13 points. It was the first series title for the second year team.
Mario's son Michael joined Newman/Haas in 1989. Together, they made history as the first father/son team to compete in both IMSA GT and Champ Car racing, as for the former, it was their fourth time in an endurance race together as co-drivers. Mario finished seventh in points for the 1991 season, the year that Michael won the championship. Mario's last victory in IndyCar racing came in 1993 at Phoenix International Raceway, the year that Michael left Newman/Haas to race in Formula One. The win made Mario the oldest recorded winner in an IndyCar event, 53 years, 34 days old. Andretti qualified on the pole at the Michigan 500 later that year with a speed of 234.275 miles per hour. The speed was a new closed course world record. Andretti's final season, in 1994, was dubbed "The Arrivederci Tour." He raced in the last of his 407 Indy car races that September.