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While working at local market stalls, Statham began practising Chinese martial arts, kickboxing, and karate recreationally in his youth. An avid footballer and diver, he was a member of Britain's national diving team and competed for England in the 1990 Commonwealth Games. Shortly after, he was asked to model for French Connection, Tommy Hilfiger, and Levi's in various advertising campaigns.

Statham's history of working at market stalls inspired his casting in the Guy Ritchie crime films Lock, Stock and Two Smoking Barrels (1998) and Snatch (2000). Both films were commercial hits, and they helped catapult Statham to stardom. He played supporting roles in the American action films Turn It Up (2000), Ghosts of Mars and The One (2001). From 2002 to 2008, he played the title role in the first three films in the Transporter film series (2002–2008), which solidified his status as an action star. In 2003, he appeared in the ensemble heist action film The Italian Job. He went on to play leading roles in the commercially successful films Crank (2006), The Bank Job (2008), The Mechanic (2011), Homefront (2013), Mechanic: Resurrection (2016), The Meg (2018), Wrath of Man (2021), Meg 2: The Trench (2023), and The Beekeeper (2024).

Statham has also starred as Lee Christmas in the ensemble action film series The Expendables (2010–2023) and as Deckard Shaw in the Fast & Furious franchise (2013–2023), including the spin-off Hobbs & Shaw (2019), which he co-produced. His voice acting work includes the documentaries Thai Boxing: A Fighting Chance (2002), Truth in 24 (2008) and its 2012 sequel, and the animated film Gnomeo & Juliet (2011).