Smith was selected by the Tennessee Titans in the sixth round (176th overall) of the 2010 NFL Draft. He was the first ever player from FAU to be drafted. He was signed to a four-year contract on June 17, 2010.
Smith made his NFL debut on November 21, 2010 against the Washington Redskins after starter Vince Young left the game with an injured throwing hand, completing 3-of-9 passes for 62 yards and one interception. Titans head coach Jeff Fisher later declared that Smith would become the team's starting quarterback due to Young's season-ending thumb surgery and Kerry Collins' calf injury. His first start was in a 20-0 shutout loss to the Houston Texans. Smith had 17 completions in 31 passes for 138 yards and was intercepted three times, all by CB Glover Quin.
Smith did not have one snap during the 2011 regular season.
In 2012 he stepped in for Matt Hasselbeck and went 3-of-5 for 34 yards. He was waived/injured by the Titans on August 31, 2013. He was re-signed the next day, and put on the team's practice squad.
Rusty Smith, who during a 2013 program at Lipscomb University discussed his faith values, is married to Nicole Smith. As of 2015 the couple has two children. The Smiths attend Grace Chapel in Leipers Fork, TN.