Lowes won the 2010 British Supersport Championship riding a Honda CBR600RR, claiming five victories at circuits including Brands Hatch, Knockhill, Cadwell Park, Croft, and Silverstone, along with five podium finishes. He moved to the Supersport World Championship full-time in 2011, signing for the Parkalgar Honda team and scoring six podiums in his first complete season to finish sixth overall with 129 points. In 2012, riding for Bogdanka PTR Honda, he claimed two victories at Donington Park and Aragon.
Lowes joined Yakhnich Motorsport on a semi-works Yamaha for 2013 and delivered a championship-winning campaign. He clinched the Supersport World title with one round remaining at Magny-Cours, finishing second in the race to seal the title. The 2013 championship confirmed him as one of the standout talents on two wheels.
Lowes moved to the Moto2 World Championship in 2014 with the Speed Up team, beginning an extended Grand Prix career in the intermediate class. After two seasons with Speed Up, he signed a three-year contract backed by Aprilia from 2016 with Gresini Racing, including the benefit of being Aprilia's official MotoGP test rider. His anticipated move to the premier class for 2017 and 2018 was cut short when Aprilia exercised an early release option mid-way through 2017, replacing him with Scott Redding for the following season.
Lowes returned to Moto2 in 2018 with the Swiss Innovative Investors team riding a KTM, finishing 16th in the standings with 49 points. He rejoined Gresini for 2019 before making the move to Team Estrella Galicia 0,0 Marc VDS for 2020 — a relationship that would endure through to 2023. His time at Marc VDS produced his best sustained Grand Prix results, establishing him as a consistent points scorer and occasional front-runner in the Moto2 field. A serious shoulder injury sustained at the 2022 British Grand Prix practice session forced him to miss the final two rounds of that season.
For 2024, Marc VDS transitioned into the Superbike World Championship, and Lowes made the switch with them, competing aboard a Ducati Panigale V4 R. The move placed him in direct competition with his twin brother Alex Lowes for the first time at an international level.
Sam Lowes's career spans two distinct phases: a dominant world-championship-winning period in Supersport, and a lengthy Moto2 career that included a brief foray into the MotoGP support role as Aprilia's test rider. His combination of a Supersport world title and a decade of Grand Prix experience, alongside the unique distinction of being one half of a competitive motorcycle-racing twin partnership, marks him as a notable figure in British motorcycle racing history.