KTM had long been established in off-road and endurance motorcycle sport before committing to road racing's premier class. In September 2014, KTM motorsport director Pit Beirer announced an intention to enter MotoGP for the 2017 season, even though development had not yet begun. The V4-engined KTM RC16, designed around a distinctive steel trellis frame chassis, was first track-tested in October 2015 at the Red Bull Ring with Alex Hofmann as the initial test rider.
Subsequent testing involved riders Mika Kallio, Randy De Puniet, Karel Abraham, and Thomas Lüthi at circuits including Circuit Ricardo Tormo, Circuito de Jerez, Brno Circuit, Misano, and Mugello. The team publicly presented the RC16 before the 2016 Austrian Grand Prix, and Kallio made a wildcard appearance at the 2016 Valencian Grand Prix — the machine's first official race start — qualifying 20th before a rear wheel sensor failure forced his retirement.
Final pre-season testing saw Pol Espargaró and Bradley Smith take the RC16 through official winter tests at Sepang, Phillip Island, and Losail ahead of the 2017 season opener.
KTM made their MotoGP debut at the 2017 Qatar Grand Prix, with Espargaró and Smith qualifying 22nd and 23rd. The team scored first points in Argentina, finishing 14th and 15th. Espargaró achieved the team's first top-ten finish at the Czech Republic Grand Prix with a ninth-place result, a milestone he repeated at Australia. Progress was incremental but demonstrable across the season.
KTM raised expectations for their second year. Espargaró scored points in seven consecutive races to open the season. At the Valencian Grand Prix, Espargaró claimed KTM's first premier-class podium, an achievement the manufacturer reached at the same round where Smith scored a personal best of eighth place in the wet conditions. It was KTM's most successful day in Grand Prix road racing to that point.
Johann Zarco was recruited to replace Smith for 2019 but announced mid-season that he would not continue for 2020. Zarco stood down from the remaining races from September onwards, with test rider Kallio substituting.
The team's breakthrough arrived on 9 August 2020 when Brad Binder won the Czech Grand Prix at Brno in dry conditions, giving KTM their first MotoGP victory. It was also KTM's first podium finish in dry weather at the premier level. The team repeated the feat at the season finale in Portugal.
Central to KTM's long-term MotoGP strategy is the KTM GP Academy, a talent development system designed to identify and nurture riders from junior series such as the Red Bull MotoGP Rookies Cup, the Northern Talent Cup, and the Austrian Junior Cup through Moto3 and Moto2 before elevating them to MotoGP. The academy operates in cooperation with satellite teams Red Bull KTM Ajo and Red Bull KTM Tech3. Notable graduates include Brad Binder, Miguel Oliveira, Remy Gardner, and Augusto Fernandez. Pedro Acosta won two junior championships in three seasons before graduating to MotoGP under the academy's structure.
Red Bull KTM Factory Racing operates distinctively in the MotoGP paddock through its use of the steel trellis frame chassis, its bright orange livery associated with KTM's brand identity, and Red Bull's prominent sponsorship. The factory team operates alongside the satellite Red Bull KTM Tech3 entry as part of KTM's broader Grand Prix structure.