Bezzecchi won the Italian Moto3 championship in 2015, and also made his debut in the 2015 FIM CEV Moto3 Junior World Championship that season. He ended the year 16th in the standings with 29 points, finishing in the top ten on three occasions. In the 2016 FIM CEV Moto3 Junior World Championship he again finished in the top ten three times, scoring 31 points and finishing 18th in the standings.
Bezzecchi made his Moto3 World Championship debut in 2015 with two wild-card appearances, finishing 26th in Qatar and retiring at the Grand Prix of Italy. In 2016 he again competed in two races, retiring in Austria and finishing 24th in Great Britain.
In 2017 Bezzecchi competed full time for Mahindra CIP, teammate of Manuel Pagliani. He had a slow rookie season until Japan, where he took third place — his maiden Moto3 podium — and ended the year with 20 points and 23rd in the standings.
For 2018 Bezzecchi switched to Prüstel GP. He won three races (Argentina, Austria, and Japan), finished second five times and third once, and took two pole positions. The season yielded nine podiums, 214 points, and third in the overall championship standings.
Bezzecchi moved to Moto2 for 2019, partnering Philipp Öttl at Red Bull KTM Tech3. His rookie year was difficult — he scored points only four times and ended the season with 17 points and 23rd in the standings.
For 2020 Bezzecchi joined the newly formed Sky Racing Team VR46 alongside Luca Marini. The pair won the teams' championship by 113 points with five race wins between them (Marini three, Bezzecchi two). Bezzecchi won in Austria and Valencia, finished second in Misano and Rimini, and added third in three further races — seven podiums and 184 points, fourth in the championship.
Following Marini's promotion to MotoGP, Bezzecchi's 2021 teammate was Celestino Vietti. He had a well-balanced season, winning in Austria, finishing second in Jerez and Silverstone, and third in Le Mans, Mugello, Germany, and Austin. He ended the year third in the riders' championship with 214 points.
For 2022 Bezzecchi moved to the premier class with Mooney VR46 Racing Team, partnering Luca Marini. He took his first MotoGP podium at the Dutch TT and his first MotoGP pole position at the Thailand Grand Prix.
In 2023 Bezzecchi took his first MotoGP win at the Argentine Republic Grand Prix in rainy conditions, briefly leading the championship for the first time in the premier class. He won the 1000th MotoGP Grand Prix at the French Grand Prix — his second win of the season — and a third win came in India, rounding out a breakthrough season in third place overall.
On 24 June 2024 it was announced that Bezzecchi would join Aprilia Racing for 2025 and 2026 alongside Jorge Martín, with whom he had fought for the 2018 Moto3 championship. After a difficult start to 2025, Bezzecchi won the British Grand Prix from 11th on the grid — his first win in over 600 days since the 2023 Indian Grand Prix. He then recorded two second-place finishes in Assen and Brno, missing three successive podiums only due to a crash at the German Grand Prix. These results left him fourth in the standings at the summer break, the highest-placed non-Ducati rider.
On return from the break, Bezzecchi took his first pole position with Aprilia at the Austrian Grand Prix — a track traditionally not suited to the RS-GP — and finished fourth in the sprint and third in the feature race. He went on to claim further pole positions at the San Marino, Indonesian, Portuguese, and Valencian Grands Prix, winning the last two.
At the start of February 2026, Bezzecchi signed a two-year contract extension to remain at Aprilia through the 2027 and 2028 seasons. He began the 2026 season by winning the first three grands prix in Thailand, Brazil, and the USA, leading the championship by five points over teammate Jorge Martín. By leading the US Grand Prix, Bezzecchi broke Jorge Lorenzo's record for most consecutive laps led.
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