Hornaday came from a racing family: his father Ron Hornaday Sr. was a two-time NASCAR Winston West Series champion. He began racing go-karts and motorcycles before competing at Saugus Speedway. In 1992, he won the NASCAR Southwest Series championship and the series' Most Popular Driver award, repeating as champion in 1993 to become the only driver to win consecutive Southwest Series titles until Jim Pettit matched the feat in 2004–2005. Hornaday's Winston Cup debut came in 1992 at the Save Mart 300K at Sears Point, starting seventeenth and finishing 32nd.
Hornaday's national breakthrough came when Dale Earnhardt signed him to drive the No. 16 Chevrolet for Dale Earnhardt Inc. in the inaugural NASCAR SuperTruck Series in 1995. He won six races and four poles in the series' first season. In 1996, backed by NAPA Auto Parts, he won four races and the series championship. Despite seven wins in 1997, he finished fifth in points before reclaiming the title in 1998 with six wins and sixteen top-five finishes in 27 races. His 1999 season included winning the 100th race in Truck Series history at Evergreen Speedway.
Earnhardt promoted Hornaday into the Busch Series for 2000, where he won at Nazareth Speedway and Indianapolis Raceway Park, finishing fifth in points and second to Kevin Harvick for Rookie of the Year. When Earnhardt reorganized his program for 2001 and gave the Busch seat to Michael Waltrip for the Cup Series, Hornaday signed with A.J. Foyt Racing in Winston Cup but struggled, finishing 38th in points.
After time with Richard Childress Racing's truck team (2003–2004) — where he won at Nazareth and Milwaukee and posted strong top-ten rates — Hornaday joined Kevin Harvick Incorporated in 2005. Running as KHI teammates from 2005 through 2011, Hornaday won his third championship in 2007 by overcoming a 29-point deficit against Mike Skinner on the final weekend, and his fourth in 2009 — clinching the title before the season finale, a feat not achieved in the series since Greg Biffle in 2000.
The 2009 title run was particularly notable. On June 20 — his 51st birthday — Hornaday won the Copart 200 at Milwaukee Mile. On July 24, he became the first Truck Series driver to win four consecutive races. On August 1 at Nashville Superspeedway he won a fifth straight race, placing him alongside Richard Petty and Bobby Allison as the only NASCAR drivers to win five consecutive races across the three major series. He clinched his fourth title on November 13, joining Jeff Gordon, Richard Petty, Dale Earnhardt, and Jimmie Johnson as the only drivers across NASCAR's three major series with four or more championships.
In 2011, a rivalry with Kyle Busch came to a head at Texas Motor Speedway when Busch deliberately drove into Hornaday's truck while under caution, pushing him into the wall and mathematically eliminating him from championship contention. Busch was suspended from two events that weekend. The incident brought significant attention to conduct standards in the Truck Series.
Hornaday ran for Joe Denette Motorsports and NTS Motorsports in 2012–2013, the latter season ending with a $25,000 fine and points penalty after he intentionally wrecked rookie Bubba Wallace under caution at Rockingham. He drove briefly for Turner Scott Motorsports in 2014 before the team's dissolution. A short Sprint Cup return with The Motorsports Group in 2015 produced limited results and Hornaday stepped away from NASCAR.
April 8, 2010 was declared Ron Hornaday Jr. Day in Palmdale, where a roundabout at the Palmdale Auto Mall was named in his honor. He was inducted into the NASCAR Hall of Fame in the Class of 2018, the first Truck Series driver to receive the honor. After retiring from competition, Hornaday founded Team Hornaday Development, a driver development program, and Hornaday Race Cars, a dirt modified chassis-building operation. His son Ronnie Hornaday also raced in NASCAR. Hornaday was diagnosed with Graves' disease during his career and used testosterone cream as part of his treatment, a fact he acknowledged publicly in 2008.