Smith grew up in Cato, New York and began his racing career at the age of four, when he began racing go-karts and microds. Over the next several years, he won numerous regional and state championships. In 1995, he and his family moved to Mooresville, North Carolina to allow Smith to advance his career. He joined the World Karting Association and continued to win.
Smith began his NASCAR career racing in the Craftsman Truck Series in 2002. He also made his Busch Series debut at Memphis Motorsports Park, starting 16th but finishing 39th after a wreck. Smith moved to the Busch Series in 2003 for a full-time ride. Regan Smith made his Nextel Cup debut at the Food City 500 at Bristol Motor Speedway, finishing 25th in NASCAR’s first Car of Tomorrow race.
Smith lost out his first win at Talladega Superspeedway because on the final lap, in the trioval, he passed Tony Stewart and gotten first place, but however it was announced that Smith went below the yellow line when he made the pass. The victory was given to Stewart. Smith said that he was pushed down by Stewart, which was true, but NASCAR rule is you can not pass below the yellow line even if you are forced and his pleas were ignored.
Despite finishing the season with no top ten finishes in 34 races, Smith won the 2008 Sprint Cup Rookie of the Year award. He became the first rookie driver in Sprint Cup history to finish every race entered in his rookie season.
On May 7, 2011 at the Showtime 500 at Darlington Speedway, Smith won his first Sprint Cup race, holding off Carl Edwards at the end. On a late caution, Smith stayed out on older tires while Edwards and most of the lead lap cars pitted for fresh right side tires. Smith fended off Edwards for two restarts to claim the first cup win of his career at Darlington Raceway. Smith in recalling the Talladega race he lost in 2008 said he was not worried about it anymore, and said the Darlington win meant more to him than what he would have experienced at Talladega. It was only the second time a driver had won his first Sprint Cup race in the Rebel 500, the first being Lake Speed in 1988.
Smith was set to finish the 2012 season by swapping rides with Busch, with Busch taking over Smith’s No. 78 and Smith taking over the No. 51 Chevrolet at Phoenix Racing.