Setzer made his NASCAR debut in the Busch Series in 1991, entering the All Pro 300 in his own No. 4 Ford Thunderbird. An early crash ended his day in 40th place. Additional scattered starts followed in 1992 and 1993, including part-time runs for Daniel Welch, before Setzer made his first full-time Busch Series campaign in 1994.
That 1994 season proved his Busch Series peak. Driving the No. 59 Alliance Training Centers Chevrolet for Welch, Setzer scored his first career win at South Boston Speedway and followed it two races later with another victory at Hickory Motor Speedway. He finished ninth in points and was runner-up to Johnny Benson for Rookie of the Year honors. Subsequent Busch and Nationwide Series appearances over the following years yielded no further wins, though Setzer remained a periodic presence in the series through 2011.
Setzer began running part-time in the inaugural Craftsman Truck Series season in 1995, finishing second in his debut at Milwaukee. His truck career accelerated at K Automotive Racing from 1999 onward. Running the No. 1 Mopar-sponsored Dodge Ram full-time in 1999, Setzer won three races and was in championship contention before an early-race crash at the California Speedway season finale ended his title hopes. He was named the series Most Popular Driver for 1999.
From 2001, Setzer joined Morgan-Dollar Motorsports. After two seasons finding footing, he delivered nine wins over 2003, 2004, and 2005 — his most productive stretch in the Truck Series. Across those three years he finished second in the championship standings in each season, a remarkable streak of near-misses that defined his career's most visible chapter.
He won the 2007 City of Mansfield 250 at Mansfield Motorsports Speedway with a strategy that saw him run the entire 250-lap race without a pit stop. In 2008, driving the No. 18 Dodge Ram for Bobby Hamilton Racing, Setzer won the Kroger 250 at Martinsville Speedway, his eighteenth and final career Truck Series victory. The win proved to be the last for the Dodge nameplate in the Truck Series before the manufacturer withdrew from NASCAR following 2012.
Setzer's Sprint Cup Series record was limited almost entirely to qualification attempts. His most notable Cup starts came via Bill Elliott's secondary teams in 1998, where he posted a best finish of nineteenth at Talladega Superspeedway across eight attempted starts. After a long absence, he eventually qualified for a Bristol Motor Speedway race in 2011, finishing 38th — his only other Cup start that counted.
Setzer continued making Truck Series and Nationwide Series starts into the early 2010s for various smaller teams. His 2010 Nationwide race at Talladega involved a severe crash in which his car hit the catch fence and exploded before landing on all four wheels; he was unhurt. After 2011, his active racing career effectively concluded.
Setzer's career represents the archetype of a driver who found his level in the Truck Series rather than the Cup Series — consistent, competitive over a long stretch, and capable of wins against established rivals. His three consecutive runner-up championship finishes from 2003 to 2005 remain the defining accomplishment of his career and a mark of sustained excellence at a level below NASCAR's top tier.