Lüthi was born in Oberdiessbach, Kanton Bern, Switzerland, but grew up in Emmental. Lüthi started racing pocket bikes at the age of nine. He won pocket bike championships in 1999 and 2000. In 2002, he finished second overall in the European 125cc Championship, and third in the German 125cc series.

Lüthi made his first 125cc World Championship appearance at the 2002 German Grand Prix, which he finished in 26th place.

In the 2003 Grand Prix motorcycle racing season, Lüthi was invited by Daniel Epp to ride for his team, known as the "Elit Grand Prix Team"; Epp became his manager. Lüthi scored his first podium in Barcelona and ended in second place. In 2004, he retired from four races in a row, missed four races because of injury, and scored 14 points.

Andy Ibbott of California Superbike School started training Thomas during the 2005 season. Lüthi scored his first 125cc class Grand Prix win in 2005 at Le Mans, followed by three more victories that season, including one at his team's home race at Brno, Czech Republic. On 6 November 2005 Lüthi secured his first world championship in the 125cc class, the sixth-youngest person to do so; this took place at Valencia. While using a Honda RS125R kit, Lüthi won the world championship title in the 125cc class, being five points ahead of Mika Kallio. Lüthi was voted Swiss sportsman of the year in 2005 and also won the annual "Swiss Award" in the category of sport.

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