The team's roots lie in two separate entities that eventually merged. The d'Antin MotoGP team was founded in 1999 by Spanish former racer Luis d'Antin in Madrid, initially racing in the 250cc Spanish and World Championships with Yamaha machinery and Spanish riders Fonsi Nieto and David García. The same season it fielded Norifumi Abe in the 500cc class on a Yamaha YZR500; Abe took a victory at the 2000 Japanese Grand Prix at Suzuka. José Luis Cardoso joined as second rider in 2001. The d'Antin team continued into the MotoGP era from 2002, later switching to Ducati in 2004 with 2003 Superbike World Champion Neil Hodgson and runner-up Rubén Xaus; the team's best result that year was a third for Xaus in Qatar.
Pramac Racing itself first entered MotoGP in 2002, taking over the activities of Hardwick Racing and fielding Tetsuya Harada on a Honda NSR500. In September 2002 Pramac signed a deal with Max Biaggi and Honda Racing Corporation, with the combined Pons Racing partnership listed as Camel Pramac Pons. Simultaneously Pramac entered Makoto Tamada under the Pramac Honda banner on Bridgestone tyres — the only Honda team to use them that season. Biaggi scored two wins and finished third in the championship; Tamada contributed a podium in Brazil. The Pramac-Pons arrangement continued in 2004: Tamada won twice and finished sixth overall while Biaggi added one victory and third place. Biaggi departed for Repsol Honda at the end of the season.
In 2005 d'Antin MotoGP and Pramac Racing merged to form Pramac d'Antin, racing the Desmosedici GP4 on Dunlop tyres with Roberto Rolfo. From 2006 the team received the current-spec Desmosedici GP6 with Alex Hofmann and Cardoso, though the Dunlop supply remained uncompetitive. From 2007 d'Antin became an integral part of the Pramac Group. Alex Barros delivered regular top-ten finishes and a podium at the Italian Grand Prix, ahead of works rider Casey Stoner. In 2008 the team ran under the Alice Team banner, sponsored by Telecom Italia's DSL service, with Sylvain Guintoli and Toni Elías. Luis d'Antin resigned at the German Grand Prix at the Sachsenring.
From 2009 the team reverted to the Pramac Racing name and raced exclusively on Ducati machinery for fifteen years. A long succession of riders passed through the squad, including Aleix Espargaró, Loris Capirossi, Randy de Puniet, Andrea Iannone, Danilo Petrucci, Scott Redding, Jack Miller, and Francesco Bagnaia. In 2013 the team was elevated to factory-supported Ducati status and began receiving current-specification Desmosedici hardware for at least one rider per season.
The most celebrated chapter arrived in the early 2020s. Johann Zarco and Jorge Martín joined for 2021, and Martín scored the team's first ever premier-class race victory at the Styrian Grand Prix. In 2023, Pramac Racing won the MotoGP teams' championship — the first independent team to achieve that distinction. In 2024, Martín clinched the MotoGP World Championship aboard a Desmosedici GP24, becoming the first world champion from an independent team in the MotoGP era since Valentino Rossi raced for Nastro Azzurro Honda in 2001. The team simultaneously collected the Best Independent Team award for the fourth consecutive year.
For 2025, Pramac Racing concluded its long Ducati association and moved to Yamaha, fielding factory-specification bikes for Jack Miller and Miguel Oliveira under the Prima Pramac Yamaha MotoGP banner. In June 2025 Yamaha announced that World Superbike champion Toprak Razgatlıoğlu would join the team for 2026, moving across from the BMW Motorrad WorldSBK programme, with Miller retaining his seat.