Sadler began racing go-karts at seven years old and progressed to Late Model stock cars at his local track. He recorded more than 200 total wins in his early career, claimed the Virginia State Karting Championship in 1983–84, and won the North Carolina Gold Cup in 1991–92. In 1995 he was crowned track champion at South Boston Speedway with thirteen race victories including a six-race winning streak.
Despite success in late models, Sadler struggled to attract NASCAR team owner interest. He sold his own racing equipment to fund an independent Busch Series program, running select events in 1995 and into 1996. A race at Hickory Motor Speedway in early 1996 connected him with Diamond Ridge Motorsports, and he drove for that team in the Busch Series through 1997 and 1998.
Sadler moved full-time into the Cup Series in 1999, driving the No. 21 Ford Taurus for the historic Wood Brothers Racing. He finished 24th in the standings and runner-up to Tony Stewart for Rookie of the Year. His 2000 season included a chaotic practice crash at Michigan where a blown tire sent the car into barrel rolls that reportedly exceeded the height of the catch fence.
Sadler recorded his first Cup win in 2001 at Bristol Motor Speedway — Wood Brothers' first victory in eight years. After a seventh-place finish at Bristol in 2000 and a third at Daytona in 2001, he showed enough pace to attract Robert Yates Racing, and he left Wood Brothers after 2002.
Driving the No. 38 M&M's Ford, Sadler won the pole at both Darlington and Talladega in his first Yates season. He was involved in violent crashes at Talladega in both 2003 and 2004: the 2003 incident saw his car fly into the air and flip eight times before landing on the roof, requiring precautionary airlift to hospital; the 2004 Talladega crash saw him land on all four wheels and cross the finish line in 22nd place.
The 2004 season was his best in Cup: he won at Texas Motor Speedway for his second Cup win and followed it with a victory at California Speedway, making the Chase and finishing ninth in the championship — a career high. He departed Yates Racing midway through the 2006 season for Gillett Evernham Motorsports.
Despite off-track issues including a pre-Daytona 500 points penalty for rule infractions in 2007, Sadler posted a sixth-place finish at Daytona that year. The 2008 season was difficult, yielding only two top-five finishes and landing him 24th in points. He was set to be replaced by A.J. Allmendinger in 2009, threatened a breach-of-contract lawsuit, and ultimately returned to the ride following the GEM–Petty Enterprises merger. In the 2009 Daytona 500, Sadler held the lead in the final stages before being passed by Matt Kenseth and finishing fifth.
In the 2010 season at Pocono Raceway, driving a No. 2 Chevrolet in the Camping World Truck Series for Kevin Harvick Incorporated, Sadler recorded his first NASCAR race win in six years. He was involved in a massive head-on impact in the Cup race at the same venue that weekend, which NASCAR later stated was the hardest head-on crash ever recorded in the series at that time.
Persuaded in part by former teammate Dale Jarrett, Sadler stepped down from the Cup Series after 2010 and signed with Kevin Harvick Inc. for the Nationwide Series. He finished second in the championship in 2011 with 24 top-ten finishes across 34 events.
KHI's Nationwide Series operations were absorbed by Richard Childress Racing for 2012. Sadler won three races that season — at Phoenix, Bristol, and Chicagoland — and again finished second in the championship, this time to Ricky Stenhouse Jr. After joining Joe Gibbs Racing in 2013, he won the 2014 Aaron's 312 at Talladega for his first JGR win. He joined Roush Fenway Racing in the No. 1 for 2015, then moved to JR Motorsports in 2016, where he won at Talladega (controversially after Joey Logano's spin), Darlington, and Kentucky. He made the inaugural Xfinity Chase and finished second in the championship for the third time.
In 2017, Sadler clinched the Xfinity Regular Season Championship at Richmond with a 91-point advantage over teammate William Byron, having gone winless in the regular season while leading the standings for all but two weeks. He entered the playoffs as third seed and finished second in the championship for the fourth time. He won the Xfinity Most Popular Driver award in 2011, 2016, 2017, and 2018 — the most in series history.
Sadler announced his retirement from full-time competition in August 2018. His final NASCAR start was the Rhino Pro Truck Outfitters 300 at Las Vegas in 2019 for Kaulig Racing, where he finished tenth driving a car styled after his 1993 late model.
Sadler's career is defined by sustained competitiveness across a span of three decades and five major teams in the Xfinity Series, alongside four Cup victories. His four Most Popular Driver awards in the Xfinity Series reflect a connection with fans that outlasted many of his more decorated contemporaries. In February 2026, he announced a return to racing in the SMART Modified Tour at South Boston Speedway for Sadler-Stanley Racing, co-owned with brother Hermie.