Anderson was selected in the first round of the 1979 NFL Draft, the 8th overall pick, by the St. Louis Cardinals. He had what was probably the greatest debut game in NFL history when he rushed for 193 yards. His single season 1,605 rushing yard performance was one of the few bright spots in the Cardinals' 1979 season, when they finished 5-11. He earned the first of back-to-back Pro Bowl selections that year.
In his first six seasons, Anderson rushed for over 1,000 yards in five seasons. The lone exception was in the 1982 strike-shortened season, when he rushed for 587 yards in eight games, and was on pace for well over 1,000 yards, if 1982 were a full 16 game season.
The Cardinals made the playoffs in 1982, thanks to an expanded field due to the brevity of the season. It was the franchise's first postseason appearance since 1975 and last until 1998. Anderson rushed for 58 yards on eight carries against the Green Bay Packers in the team's lone playoff game.
Injuries drastically decreased the number of games Anderson played each season, and his explosiveness as a tailback. After a year and a half, Stump Mitchell emerged as the Cards' top running back, and the expendable Anderson was traded to the New York Giants in the middle of the 1986 season. He ended up deep in the Giants' depth chart. By this time in his career, it was clear that he was better used in goal line or short yardage situations. Anderson would rush for only six yards on seven carries in the 1986 playoffs, but did score a rushing touchdown in the Giants' victory over the Denver Broncos in Super Bowl XXI.
In his first two and a half seasons with New York, Anderson did not fumble once in his 100 offensive touches. In 1989, Anderson become the top running back for Bill Parcells' ball control offense and was named NFL Comeback Player of the Year. He scored a career high 14 rushing touchdowns, and rushed for 1,023 yards on 325 carries. He was also the top running back for the Giants the following year, when they won Super Bowl XXV, and was named Super Bowl MVP for his 102 yards and a touchdown on 21 carries. As a testament to the Giants' ball control strategy, their time of possession was double that of the Buffalo Bills, their opponents, in the first Super Bowl without a turnover. Anderson is one of only four running backs in NFL history to score rushing touchdowns in two Super Bowls and win Super Bowl MVP (only Franco Harris and John Riggins accomplished this feat before Anderson, and only Emmitt Smith has achieved it since).
Anderson was replaced by Rodney Hampton in 1991. His last season was 1992. Anderson fumbled just three times in 739 touches as a Giant, from 1987-1992.
When he retired, Anderson ranked seventh in rushing TDs and eighth in rushing yards. At the 2014 season, Anderson was ranked 18th in career rushing touchdowns and is one of 29 running backs in the history of the NFL to rush for more than 10,000 yards (currently ranked 26th in career rushing yards).
As president of Ottis J. Anderson Enterprises, Anderson is also involved in several ventures and is involved with writing benefits for municipalities, school boards and privately held businesses in New Jersey.
Chris Cuomo of ABC News interviewed Anderson as part of One Moment in Time: The Life of Whitney Houston, a two-hour special on ABC shortly after the death of singer Whitney Houston. In Super Bowl XXV, Houston performed "The Star-Spangled Banner", and Anderson and then-Giants quarterback Jeff Hostetler reflected on Houston's performance in that game.