Rube began his professional football career in 1907 with the Minneapolis Marines. Rube Ursella was the true superstar of the team and had a long and successful pro football career with the Marines. He was both an offensive and defensive standout, as well as a skilled kicker and punter. Pro football shut down completely in 1918, due to the 1918 flu pandemic. In 1919 Walter Flanigan, the manager of the Rock Island Independents, was able to lure Ursella away from the Marines. With Rube came several other players as well as their offense which became known as "the Minnesota Shift". The team lost only one game that season, to the Hammond Pros. In 1921 Rube returned to the Marines, however the team was unable to play up to its previous level. He returned for two more seasons with the Independents in 1924 and 1925.
During the 1926 season, Rube played for the Akron Indians and Hammond Pros before retiring at the end of the season. He returned in 1929 to play for the Minneapolis Red Jackets before retiring, for good, after that season.