McLaren finished in third place in the World Constructors' Championship for the first time since 2012 and achieved podiums at the Austrian and Italian Grands Prix, while also claiming three fastest laps and setting a track record at the Red Bull Ring.

The updated car made its competitive début at the first race of the season, the 2021 Bahrain Grand Prix, and set two fastest laps, one pole position, and scored five podiums in total.

[17][18] Key explained that the suspension geometry of the MCL35 had been redesigned to incorporate developments the team had not been able to implement on the MCL34,[17][19] which included the repositioning of both the upper and lower wishbone elements to influence airflow over the bargeboards and floor.

[21][22] Prior to the first race of the season in Austria, McLaren revealed the addition of a rainbow graphic on the sidepod and halo in recognition of Formula One's #WeRaceAsOne campaign.

[31] Key stated in November 2020 that the planning for the switch had gone smoothly, with the MCL35M to feature "a couple of changes to architecture [made] necessary by the shape of the engine compared to this year's.

"[44] After McLaren's withdrawal from the Australian Grand Prix and the race's subsequent cancellation,[45] the season was heavily disrupted by the COVID-19 pandemic and the calendar was reorganized which delayed the car's début for several months.

[53] After Norris lost positions in the opening laps to Hamilton and Alex Albon, both McLarens ran comfortably in the top ten for the remainder of the race.

[57] In an article on strategy calls published in 2021, the team said the result was possible because of the "flawless" double-stacked pit stop allowing Norris to be in position to capitalize on Hamilton's penalty.

[78] Sainz later said that the team had discovered an overheating issue in third practice, and in order to be able to complete the race the car had to undergo bodywork changes that compromised his qualifying pace.

Norris finished fourth while Sainz attempted to catch race leader Pierre Gasly, reducing the gap to 0.415 seconds by the final lap.

After the safety car restart Sainz was involved in an accordion effect crash with Antonio Giovinazzi's Alfa Romeo, the Williams of Nicholas Latifi, and Magnussen which triggered the first red flag of the race.

[171] Sainz predicted ahead of the Sakhir Grand Prix that choosing the correct setup – particularly downforce levels – would be challenging because of the circuit's lengthy straights.

[181] Norris recovered to finish tenth after being passed by George Russell's Mercedes on the last lap, and said that he lacked the pace to challenge for higher positions,[181] which he attributed to the MCL35's struggle with dirty air.

[44][192] Journalist David Tremayne described the MCL35 as "a consistent points scorer", a characteristic that enabled McLaren to remain competitive in seeking third place in the Constructors' Championship.

[197] McLaren "substantially re-engineer[ed] some areas" of the MCL35 to adapt to 2021 regulations that reduce the overall downforce of the car, while the switch to the Mercedes power unit necessitated the redesign of hydraulics,[198] cooling, electronics,[44] pipework for air and fluids, and control boxes.

[206] Key said he was surprised no other team had implemented the workaround, but characterized it as part of a larger aerodynamic concept and did not expect it to be copied or a continuing point of controversy.

[207] In a review of 2021 development, journalists and technical analysts Mark Hughes and Giorgio Piola called McLaren's diffuser the "most original" innovation of the season.

[214] The team ran a second one-off livery at the Abu Dhabi Grand Prix in partnership with Vuse, featuring the work of local artist Rabab Tantawy.

[219] When questioned on the possibility of McLaren challenging for podiums more regularly in the 2021 season, Norris said "that's too much" and that "The Mercedes engine and back-end is a good step forward but it won't sort everything out.

[224] McLaren was generally quick in pre-season testing (held at the Bahrain International Circuit), setting several fastest laps without any major reliability issues.

"[225] Both drivers appeared quick in practice for the Bahrain Grand Prix, but said they were dissatisfied with the MCL35M's handling and balance, and expected the team would be slower than Mercedes and Red Bull and closer to the rest of the field when it came to qualifying and the race.

[247] Norris qualified ninth, a result he was disappointed with after he was impeded by Haas driver Nikita Mazepin in Q1 and had to use an extra set of soft tyres, limiting the running he could do in Q3.

[262] Major McLaren Group shareholder Mansour Ojjeh died shortly before the 2021 French Grand Prix, and his name was featured on the side of the cars as a tribute.

[270] Norris allowed Pérez and Bottas to pass him in the opening laps, as McLaren did not believe the MCL35M had the pace to maintain position ahead of the Red Bull and Mercedes cars, and finished fifth.

The penalty was served on-track at Norris' scheduled pit stop, and he recovered to overtake Hamilton for third place on lap 52 and finished on the podium for the third time in the 2021 season.

[286] McLaren delivered their final major upgrade to the MCL35M at the Hungarian Grand Prix in order to focus on the car's successor;[287] the package featured revised bargeboards.

Norris set the fastest times in Q1 and Q2, but lost control of his car at Eau Rouge and crashed heavily, ending his qualifying session and damaging his gearbox.

[317] Ricciardo qualified seventh and Norris eighth for the United States Grand Prix, with both being promoted a place due to another engine penalty for Bottas.

[329] Norris and Ricciardo qualified eighth and ninth respectively for the third and final sprint race of the season at the São Paulo Grand Prix, but were both promoted a place by Hamilton's disqualification.

FIA Formula 2 Championship driver and Red Bull Junior Team member Jehan Daruvala tested the car over two days at Silverstone Circuit prior to the British Grand Prix, completing 130 laps.