Having won the Russian Karting championship, Mazepin began international karting in 2011 at the Andrea Margutti Trophy. In 2013 he finished fourth in the KFJ category of the WSK Super Master Series. In 2014, his final year of karting, he finished runner-up to Lando Norris at the Karting World Championship.
Mazepin made his car racing debut in the MRF Challenge Formula 2000 at the end of 2014, taking his first podium in only his second race. He then competed in the Toyota Racing Series with ETEC Motorsport, finishing 18th in the standings. He subsequently raced in the Formula Renault Northern European Cup for Josef Kaufmann Racing alongside Louis Delétraz, Kevin Jörg, and Dries Vanthoor, scoring one podium — a third at the Red Bull Ring — and finishing twelfth.
In 2016 Mazepin competed in the FIA Formula 3 European Championship for Hitech Grand Prix, scoring four points finishes and finishing 20th, last of all full-time entrants. During the season he struck Callum Ilott in the face following a track incident, receiving a race ban for the first race at the Hungaroring. Frits van Amersfoort of Ilott's team called the ban "a ridiculous decision by the stewards." Mazepin was retained for 2017, improving significantly to 108 points and three podiums, finishing tenth — one place behind teammate Ralf Aron.
Mazepin moved to the GP3 Series with ART Grand Prix in 2018, alongside Callum Ilott, Jake Hughes, and eventual champion Anthoine Hubert. He won four races — the most of any driver that year — and finished second in the championship, sixteen points behind Hubert, while helping ART secure the teams' title.
In 2019 Mazepin joined ART Grand Prix in Formula 2 alongside Nyck de Vries. The season was marked by a collision he caused with Nobuharu Matsushita in the Sochi sprint race; he ended 18th with eleven points. In 2020 he signed for the new Hitech Grand Prix team alongside Luca Ghiotto. His first podium came at the Hungaroring with second place, before taking his first F2 victory in Britain. He also won the feature race at Mugello. On the final lap of the Belgian feature race, he pushed Carlin driver Yuki Tsunoda wide and received a five-second time penalty that denied him victory. He finished fifth in the 2020 championship with Hitech.
Mazepin served as test driver for Sahara Force India from 2016 to 2018, logging 100 laps at the Hungaroring in 2017 and 51 laps there in 2018. In 2019 he topped the timing sheets at the Barcelona in-season test for Mercedes, driving the W10 to a time of 1:15.775.
Mazepin joined Haas for 2021, choosing race number 9. He competed under a neutral flag representing the Russian Automobile Federation following the Court of Arbitration for Sport's upholding of a World Anti-Doping Agency ban on Russia at World Championships due to state-sponsored doping.
His debut at the Bahrain Grand Prix ended on the first lap when he lost control on the kerb at turn three. He spun twice in practice and blocked Antonio Giovinazzi in qualifying at the Emilia Romagna Grand Prix, then received a five-second penalty for blocking Sergio Pérez under blue flags at the Portuguese Grand Prix. His first race beating teammate Schumacher came in Monaco. His career-best finish of fourteenth came at the Azerbaijan Grand Prix, helped by four retirements in the field. He missed the season finale at Yas Marina due to a positive COVID-19 test on race day and was not replaced. Mazepin ended the season 21st in the standings with no points, as the VF-21 scored none all year.
On 5 March 2022, Haas terminated Mazepin's multi-year contract along with title sponsor Uralkali's sponsorship, citing the Russian invasion of Ukraine. Mazepin stated his "ongoing willingness to accept the conditions proposed in order to continue were completely ignored" and described the sports sanctions as "cancel culture" against Russia. In July 2022 he sued Haas in a Swiss court for unpaid wages. Two years of legal proceedings followed, culminating in Haas having their assets seized at the 2024 Dutch Grand Prix amid their battle with Uralkali. Although his EU sanctions were dropped in March 2024, Mazepin chose not to pursue an F1 return, stating "the time has come to write the next act of my life as an adult."
Mazepin participated in a test with Dakar Rally-winning truck team Kamaz Master in July 2021. He trained with former Dakar quad category winner Sergey Karyakin and his Snag Racing team, with Karyakin noting that Mazepin knew "how to read the lines perfectly" on sand. Mazepin made his rally debut at the Ladoga Trophy in June 2022, then competed in the Silk Way Rally, winning his class in the T3 category for Snag Racing with a stage victory on the seventh leg. Scheduling conflicts kept him from the 2023 Silk Way, though he finished second at the Baja Astrakhan that year and second again at the 2024 Denis Davydov Baja. He was named a Master of Sports of Russia on 29 May 2025 in recognition of his rally success.
In 2023 Mazepin returned to international motorsport with 99 Racing in the Asian Le Mans Series, competing under a neutral flag. At the opening Dubai race, he and teammates Neel Jani and Gonçalo Gomes finished on the podium, with Jani narrowly losing second to Charlie Eastwood. He and Jani finished fourth in the LMP2 driver's championship. In 2025, Mazepin joined the Middle East Trophy to drive for Graff Racing.
On 9 December 2020, Mazepin posted an Instagram story in which he appeared to inappropriately grope a woman's breasts. Haas rebuked his actions as "abhorrent." Mazepin issued an apology, later deleted, and reiterated in March 2021 that he understood his actions were wrong. The controversy produced the hashtag "#WeSayNoToMazepin" on Twitter.
In March 2022, Mazepin and his father were included on EU sanctions lists following the Russian invasion of Ukraine; UK and Canadian sanctions followed. In April 2022, a residential compound in Portisco, Sardinia worth more than $114 million was seized by Italian authorities. In 2023 Mazepin launched legal challenges against the EU, UK, and Canadian sanctions. A UK high court rejected a bid to suspend the sanctions on an interim basis in June 2023. In September 2023, the EU partially lifted the sanctions to permit travel for motorsport activities. In March 2024, the EU overturned the sanctions entirely, ruling the association criterion of beyond a simple family relationship no longer applied. Following his F1 dismissal, Mazepin created "We Compete as One," a foundation to support athletes excluded for "non-sporting decisions."
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