From 2000 to 2002, he contested the national 125cc GP championships in Britain and Spain, winning the English 125cc Aprilia Championship in 2000, before moving full-time to the 250cc GP World Championships in 2002. His season on an Aprilia under the guidance of Lucio Cecchinello was turbulent, with no podium places from 15 race starts.

In 2003 Stoner moved to the 125cc GP category. Here, working again with Cecchinello and Aprilia, he met with considerable success, scoring his first GP race win and three second places, finishing eighth overall at the season’s end.

Stoner met Adriana Tuchyna from Adelaide when she approached him at Phillip Island in 2003 and asked him to sign her stomach. A relationship began in 2005 when she turned 16, and they were married in Adelaide on 6 January 2007.

In 2004 Stoner joined the Red Bull KTM factory team in 125cc class and continued to improve, with another race win, two second places, three thirds, and a final championship position of fifth.

In 2005 he rejoined the 250cc world championship class, racing once again for Lucio Cecchinello’s team on a works Aprilia, Stoner emerged toward the season’s end as a serious threat to championship leader Dani Pedrosa; a threat that only dissipated with a crash at Stoner’s home Grand Prix of Phillip Island, allowing Pedrosa to establish an insurmountable points lead. Stoner went on to claim a solid second place in the overall championship standings, with an impressive five race victories for the season.

In October 2005, Stoner, along with Lucio Cecchinello’s team, reportedly had an agreement to move to the MotoGP class in the upcoming season with support from Yamaha. After the season ended, he received an offer from the Honda Pons team and tested the Honda RC211V bike with them at Valencia. However, in December 2005, Stoner re-signed with Cecchinello’s team after Honda Pons failed to secure sponsorship for the upcoming season. The team then made an agreement with LCR Honda to run the RC211V for Stoner in 2006.

Stoner showed signs of feeling under-appreciated by the general public. He was angered by consistent suggestions that the bike and tyres had a bigger role in his success than he did, and unhappy at being booed at Donington in 2007 and 2008.

In 2008, Stoner took the #1 decat on his bike. Stoner opened the 2008 season with a victory at Qatar, before a run of two races without a podium. He returned to the podium with a second place at Mugello, before starting a run of seven successive pole positions. He turned three of them into successive victories—a lights-to-flag win at Donington, leading every lap at Assen six days later, and recovering from a huge Friday crash at Sachsenring to win in the wet after Dani Pedrosa crashed, moving to within 20 points of the championship lead. However, successive crashes while fighting for the lead at Mazda Raceway Laguna Seca (where he remounted to finish second to Valentino Rossi), Brno and Misano ensured that he could not defend the title successfully. Stoner finished the 2008 season with six wins and was runner-up to Rossi with 280 points, the highest number of points ever gained without taking the title at the time.

In August 2008 he was criticised for his former Ducati team’s association with tobacco company Philip Morris.

Stoner was initially diagnosed with anaemia and an inflammation of the stomach lining. Stoner later disputed the diagnosis, however, and, after continuing to struggle with the condition, he announced on 10 August 2009 that he would miss rounds 11, 12 and 13 in Brno, Indianapolis and Misano, respectively, in an attempt to recover from the illness, he was subsequently diagnosed as lactose intolerant. Mika Kallio was chosen as Stoner’s replacement for the three races. Stoner returned to racing late in the 2009 season, placing second in the Portuguese Grand Prix and an emphatic first in the Australian Grand Prix, which he led throughout. At interview following the Australian Grand Prix, Stoner said that he experienced none of the premature tiredness that had dogged him earlier in the 2009 season. He followed this up with another first place in the wet at the Malaysian Grand Prix. At the last round of 2009 at Valencia, Stoner dominated all practice and qualifying sessions to take pole, only to crash on cold tyres on the warm-up lap and miss the race. Stoner ended the season with four victories, and eight podiums in total, leading to a fourth-place finish in the riders’ championship.

Stoner remained with Ducati for the 2009 season with new teammate Nicky Hayden, with a further option for a 4th season in 2010. A strong start to the season left Stoner in a three-way battle with the Fiat Yamaha duo of Rossi and Jorge Lorenzo, before he was struck by a mystery illness which caused him to feel tired long before the end of races, leaving him 16 points behind Rossi and 7 behind Lorenzo after the US Grand Prix at Laguna Seca on 5 July.

Stoner raced with the Repsol Honda Racing Team in 2011, with teammates Dani Pedrosa and Andrea Dovizioso. In preseason testing in Malaysia, Stoner was quickest in all three sessions, closely followed by Pedrosa and reigning world champion Jorge Lorenzo. Stoner won the season-opening race in Qatar from pole position, and had been quickest in each of the free practice sessions held before qualifying. Stoner took pole position for the Spanish Grand Prix, but had been running second behind Marco Simoncelli when he was taken out by the Ducati of Valentino Rossi in wet conditions. Stoner won three out of the first five rounds of the season, with victories in Le Mans and Catalunya to add to his Qatar victory. Stoner added victories at Silverstone in damp conditions, and Laguna Seca, to hold a 20-point lead over Jorge Lorenzo with eight races to go in the season.

At the Czech Republic Grand Prix in August 2011, Stoner announced that his wife was pregnant with their first child. The baby, named Alessandra Maria, was born on 16 February 2012, the same birthday as Stoner’s long-time rival Valentino Rossi. On 6 October 2017, their second daughter Caleya Maria’s birth was announced by Stoner on social media.

On 17 May 2012, during the pre-event press conference at the French Grand Prix, Stoner announced that he would retire from MotoGP at the end of the 2012 season. Stoner stated that he no longer enjoyed competing in the series, which was one of the contributing factors to his retirement. Getting away from the political stress of MotoGP, as well as having a desire to spend more time leisurely with his family were further reasons for his retirement. In a June 2014 interview, Stoner said he was enjoying his life away from the sport with his family and had no regrets about his retirement, further dismissing any chances of a comeback.

Before the 2012 Australian Grand Prix, the Phillip Island Grand Prix Circuit named the third corner “Stoner Corner”.

After announcing his retirement from MotoGP, rumours persisted throughout the year that Stoner would debut in touring car racing in 2013; specifically the Australian V8 Supercars series. Such a switch is a rare but not unprecedented move; as fellow Australian world motorcycling champion Wayne Gardner retired from motorcycle racing in 1992 and made his touring car debut the following year. The rumours intensified when V8 Supercars team Triple Eight Race Engineering announced that Red Bull; a long term sponsor of Stoner, would be the major sponsor of the team from 2013 onwards, replacing Vodafone. After numerous denials, in January 2013, Stoner announced that he would indeed move to touring car racing on a one-year contract with Triple Eight Race Engineering. Stoner would race in the second tier Dunlop V8 Supercar Series for the 2013 season.

On 27 February 2013, two days before his debut at the Adelaide Street Circuit, Stoner unveiled his car, sponsored by Red Bull and Pirtek. His car would be a Holden VE Commodore, the same car that was driven to victory in the 2010 Supercheap Auto Bathurst 1000 by Mark Skaife and Craig Lowndes. His cameo season was unsuccessful, finishing in the mid-field most races with a highest finish of 5th at Queensland Raceway. He finished the season 18th in the standings with 704 points.

In 2013, Stoner signed with Honda as a test rider to aid in the development of new machinery on a limited basis through to the end of the 2014 season. He renewed his contract again in 2015 for another season of test riding through to January 1, 2016.

Stoner was named the 2008 Young Australian of the Year for his 2007 MotoGP performance. On 10 June 2013, Stoner was appointed a member of the Order of Australia for significant service to motorcycle racing.

The FIM named him a Legend in October 2013 prior to the 2013 Australian motorcycle Grand Prix.

Stoner wore sponsored protective gear from Spidi between 2002 and 2005, and Alpinestars between 2006 and 2012. After announcing his retirement from MotoGP, Stoner still wore sponsored gear from Alpinestars, between his debut of the Australian V8 Supercars in 2013 and associated with the HRC with the tests of development new machinery for Honda RC213V.

After three years retired from MotoGP, on 27 March, HRC announced that Casey Stoner was to return to motorcycle racing in 2015. In July, Stoner competed at the Suzuka 8 Hours where he rode the Honda CBR1000RR. His teammates were World Superbike rider Michael van der Mark and MFJ All Japan Road Race JSB100 Championship and HRC test rider Takumi Takahashi. The team qualified for the race in fourth position. With his team leading the race, Stoner suffered a violent crash due to a throttle malfunction which forced him to dump his bike into a guard barrier. The crash saw their race come to an end.

In October 2015, he was inducted into the Sport Australia Hall of Fame.

In 2016 Casey Stoner returned to the Ducati Corse Team as a test rider for the 2016 MotoGP season, ending his five-year tenure with Honda. Stoner’s main role with Ducati is being a test rider and it has been further proposed that he may appear in some races as a wild card entry. Whether it could ultimately lead to a 2017 permanent return is yet undisclosed. Stoner participated in the official pre-season tests at Malaysia and was the fastest Ducati rider on the grid. He finished the final day of testing with the 5th-best time overall.

In 2019 Stoner revealed he was living with Chronic Fatigue Syndrome also known as ME Myalgic Encephalomyelitis. In 2020 Casey Stoner became an ambassador for Emerge Australia, an advocacy and support organisation for ME/CFS.