In the spring of 2004, Rupp won his 5000 meters heat against college runners at the Stanford Cardinal Invitational with a time of 13:55.32, fourth-best in U.S. prep history.

He went on to break the Oregon state records for the 1500 m (3:45.3) and the mile (4:01.8), the latter mark being the ninth-best in American high school history at the time.

On July 31 in Heusden-Zolder, Belgium, he broke Gerry Lindgren's 40-year-old U.S. high school record for the 5000 m by almost seven seconds, with a time of 13:37.91 for the event.

On April 20, 2007, Rupp made a huge comeback in the last 200 meters of a 5000-meter race to edge out Chris Solinsky, improving his personal best to 13:30.

On April 29, 2007, Rupp defeated a stellar field to win the men's 10,000 m at the Payton Jordan Cardinal Invitational at Stanford.

Rupp made his global senior debut at the 2007 World Championships in Athletics and came in 11th at the 10,000 m.[7] A few months later, Rupp finished second – one second behind the winner, Liberty University's Josh McDougal – and led the Oregon Ducks to the 2007 NCAA men's cross country team championship.

Indoors, he joined the sub-4:00 club for the one-mile run on March 7 with a time of 3:57.86 at the Husky Last Chance Qualifier Meet in Seattle.

[9] At the NCAA indoor nationals, he won an unprecedented three events: the 5000 m (13:41.45), the distance medley relay (running a 3:57.07 as the 1600 m anchor leg only 90 minutes after his 5000 m victory), and the 3000 m (7:48.94) the next day.

[12] Having earned himself a place on the U.S. team for the 2009 World Championships in Athletics, Rupp announced that he was turning pro and that Michael Johnson would be his agent.

[14] Rupp knocked more than 20 seconds off his previous 10,000 m personal best with a time of 27:10.74 in Palo Alto, California, at the Payton Jordan Stanford Invitational.

[15] Rupp competed on the 2010 IAAF Diamond League circuit and made a series of improvements to his personal records: he broke four minutes for the one-mile run at the Pre Classic, running it in 3:57.72,[16] set an outdoor 3000 m personal best of 7:43.24 at the London Grand Prix,[17] and then improved his 5000 m time to 13:07.35 at the season-ending Weltklasse Zürich meeting.

At the 2011 USA Outdoor Track and Field Championships, he once again retained his national 10,000 m title, running the last 800 meters in a quick 1:52.59 to seal his victory, and came back the next day to finish third in the 5000 m. In July, he improved his 5000 m personal best to 13:06.86 at the Diamond League meeting in Birmingham, England, out-sprinting the reigning world cross country champion, Imane Merga, for second place behind winner, Mo Farah.

He then doubled back to run the 5000 m, and though he was in the lead with Farah with a little more than a lap remaining, he was out-kicked and finished in ninth place with a time of 13:28.64.

Rupp broke Bernard Lagat's U.S. indoor two-mile run record on February 11, 2012, when he won the event at the USA Track & Field Classic meet in Fayetteville, Arkansas, in a time of 8:09.72.

[25][26] On August 4, 2012, at the London Olympic Games, Rupp took a surprise silver medal for the 10,000 m behind his training partner Mo Farah with a time of 27:30:90, after running his last lap in 53.8 seconds.

He placed sixth in the Prefontaine Classic 5000 m. At the 2013 USA Track & Field Championships, he won his fifth-consecutive outdoor 10,000 m title, finishing with a time of 28:47.32.

At the London Diamond League meet, his last event before Moscow, he raced in the Emsley Carr Mile, in which he was the top American in an international field, even though he is a 10,000 m specialist.

On August 10, 2013, at the 14th IAAF World Championships in Moscow, Russia, Rupp placed fourth in the 10,000 m final with a 27:24.39, a seasonal-best performance.

At the 2015 USA Outdoor Track and Field Championships, Rupp won his seventh-consecutive 10,000 m national title, finishing with a time of 28:11.61 – less than three seconds ahead of runner-up Ben True.

He beat second-place finisher, Meb Keflezighi, by over a minute, recording the winning time of 2:11:13 on a warm day in Los Angeles.

[45] Rupp underwent surgery on October 19 to correct a condition called Haglund's syndrome, a bony bump on his heel that was causing his Achilles tendon to fray.

[46] Controversy rose when Rupp's former coach Alberto Salazar was accused of providing his athletes with performance-enhancing drugs.

He ran with the leaders through the first 30 kilometers but could not match the move made by eventual winner, Eliud Kipchoge, finishing three minutes and three seconds behind him with a time of 2:11:41.

In September, Rupp placed third in the Great North Run – the second-largest half marathon in the world – which was won by Marc Scott.

[50] After battling repeated injuries and illness, Rupp placed 19th at the marathon at the World Athletics Championships held in July, but stated that he was improving.

[52] Rupp headed into 2023 in poor health after multiple DNFs in 2022 and running injured in the 2022 World Marathon championships.

[53] Rupp focused the rest of his year in building up for the Chicago Marathon, a race he has run 4 times including a win in 2017 and runner up finish in 2021.

[54] Rupp ran in a pack with fellow Americans Conner Mantz, Daniel Mesfun, and Sam Chelanga.

[59] In October 2019, it was announced that Salazar, as well as Nike consultant Dr. Jeffrey Brown, would be banned from the sport by the United States Anti-Doping Agency for a period of four years due to the trafficking of testosterone, the prohibited use of L-carnitine and tampering with doping controls.