Starting for three years at Syracuse University, Nance tied the school record for career touchdowns (13) and led the Orange (then the Orangemen) in rushing in 1964, scoring in ten straight games. In 1963 and 1965 Jim Nance was the NCAA heavyweight wrestling champion and received All-America honors.
Nance was a 19th round selection of the Boston Patriots in the 1965 AFL Draft, as well as a 4th round selection of the Chicago Bears in the 1965 NFL Draft. Nance signed with the Patriots. Though his rookie season was unimpressive, he led the AFL in rushing the next two seasons. He went on to become the only AFL player ever to rush for more than 1,400 yards in a season. At 6-1 and 260 pounds, Nance was a classic fullback who carried 299 times in 1966, for 17 touchdowns and 1,458 yards. That season, he rushed for 208 yards and two touchdowns in a 24–21 victory over the Oakland Raiders.
Nance was an American Football League All-Star in 1966, when he also received the league’s Most Valuable Player award, and an All-Star again in 1967 when he became the only AFL player to have consecutive seasons with over 1,000 yards, this time 1,216. He retired as the Patriots' all-time leading rusher with 60 career touchdowns, a record he still holds.
In 1974, Nance played with the Houston Texans/Shreveport Steamer of the World Football League, rushing for 1,240 yards. In 1975, he ran for 767 yards before the WFL folded. He is the all-time leading rusher in the WFL with 490 carries for 2,007 yards and a 4.1 average. He rushed for 15 touchdowns in his WFL career.