In 2000, Horner returned to America to resume a record-setting domestic career, riding with Mercury in 2000, Prime Alliance in 2002, Saturn in 2003 and Webcor Builders in 2004.

Horner decided to move to Saunier Duval–Prodir after his top-ten finish in the 2004 UCI Road World Championships because he wanted to give the Tour de France a try.

After being injured in the beginning of 2005, Horner showed strong performance in the USPRO Championships and won his first major European victory by taking the sixth stage of the 2005 Tour de Suisse.

He then earned his place on the 2005 Tour de France team and nearly won the Miramas to Montpellier stage when he and Sylvain Chavanel refused to cooperate in the final kilometers and were caught by the peloton.

[11] Horner earned the nickname "The Smiler" for his unflappable expression of happiness, even during the most excruciating physical challenges, and "The Yahoo Kid" for his wild exclamations after winning a race.

In the 2008 Cascade Cycling Classic Horner carried amateur cyclist and Nordic combined skier Bill Demong (who was from another team) with his broken bicycle to the finish line.

He and his RadioShack teammates did well at the Tour of California, with Horner putting on a particularly strong performance in the last stage of the race as a member of a final breakaway at Thousand Oaks.

His good form also resulted in a 9th place overall at the Tour de France, as the first-placed American rider, in spite of dedicating himself in the first stages to supporting his captain Lance Armstrong.

He scored a major solo victory on the 4th stage, after making significant time gains on the day's final mountain finish in San Jose.

Nibali – who had been looking to complete a Giro–Vuelta double[28] – tried to distance Horner on several occasions as they climbed into the clouds on the mountains on the Angliru with fans parting as they rode up sections so steep that the camera bikes stalled and fell leaving no TV coverage for several minutes as they struggled to catch up.

He elected not to compete in the Giro d'Italia; on June 30, 2014, Horner was named in Lampre's Tour de France squad, with Rui Costa as team leader.

However, Horner withdrew from the Vuelta ahead of the first stage due to his cortisol levels dropping below the threshold considered healthy by the Mouvement pour un cyclisme crédible, of which Lampre–Mérida is a member.

[39] In 2019, Horner joined the team of broadcaster NBC for their coverage of the Tour de France, acting as a commentator,[40] and in August 2020 started his own YouTube show called 'The Butterfly Effect'.