Montoya discussed a move to NASCAR with Chip Ganassi Racing and partner Felix Sabates in June 2006, while still under contract to McLaren in Formula One. He signed a multi-year deal on July 9 to replace Casey Mears in CGR's No. 42 Dodge Charger beginning with the 2007 season. Following Montoya's announcement before informing McLaren, the team sidelined him immediately; DaimlerChrysler intervened to broker an early contract release, reportedly involving a $5 million payment from Ganassi.
As preparation, Montoya debuted in stock cars at the ARCA Re/Max Series Food World 250 at Talladega Superspeedway, starting second and finishing third. He competed in the final three 2006 Busch Series races for CGR, with a best finish of eleventh at Memphis. His Nextel Cup debut came at the 2006 Ford 400 at Homestead-Miami Speedway, where his car caught fire after contact from Ryan Newman.
Montoya entered his first full Cup season facing a steep learning curve with the Car of Tomorrow's characteristics, particularly in traffic. He qualified 36th for the Daytona 500 and managed a nineteenth-place finish after avoiding a late accident. His first top-five came at the Kobalt Tools 500 at Atlanta. At the Toyota/Save Mart 350 at Infineon Raceway, Montoya — starting 32nd — passed Jamie McMurray for the lead with seven laps remaining and held on to win, becoming the first foreign-born Cup Series winner since Earl Ross in 1974. He finished second in the Brickyard 400 and ended the season twentieth in the standings, winning Rookie of the Year honors by 24 points over David Ragan.
In the 2007 Busch Series, Montoya drove 17 races for CGR. In the Telcel-Motorola Mexico 200 at the Autódromo Hermanos Rodríguez, he led 43 laps and bumped teammate Scott Pruett aside with eight laps remaining to win — the first foreign-born NASCAR winner since Ron Fellows in 2001.
The 2008 Sprint Cup season was difficult. CGR's overall performance fell, Montoya recorded no top-ten finishes outside road courses, and crew chief changes compounded the disruption. He openly questioned Ganassi's commitment and requested a direct meeting with the team owner in May to air his frustrations. His best result was a second at Talladega's Aaron's 499, while road course results included sixth at Infineon and fourth at Watkins Glen. He finished 25th in the final standings.
Earnhardt Ganassi Racing (formed through a CGR merger with Dale Earnhardt, Inc.) ran Montoya in a Chevrolet Impala from 2009. Under crew chief Brian Pattie's guidance, Montoya adopted a more conservative, patient approach. He recorded ten top-ten finishes, qualified on pole for the Aaron's 499 at Talladega, and entered the Chase for the Sprint Cup after finishing tenth in points at Richmond. In the Chase, he ran as high as third in the standings with six top-tens, including a second at Pocono, before a string of accidents ended his title challenge. He finished eighth in the final standings with 6,252 points — his best Cup Series championship result.
Montoya's 2010 season produced his second and final Cup Series win. At the Heluva Good! Sour Cream Dips at the Glen at Watkins Glen, he started third and led 74 of 90 laps to claim victory. He recorded eight top-tens and two poles but missed the Chase due to inconsistency. He was 17th in the standings.
A 2011 NASCAR-mandated nose change slowed CGR's cars significantly. Montoya recorded eight top-tens and finished 21st. In the 2012 Daytona 500, his trailing arm snapped and sent him crashing into a jet dryer carrying jet fuel, igniting a fire that stopped the race for two hours under caution. The season produced just two top-tens. He finished 22nd in points.
For 2013, Montoya drove the Generation 6 Chevrolet SS with Hendrick Motorsports engines. Despite mechanical problems early in the year, he secured a second-place finish at the FedEx 400 at Dover and five additional top-tens. He was 21st in the final standings — his last full-time Cup season. EGR informed him in mid-2013 that his contract would not be renewed.
In 2014, Montoya made two Cup starts for Team Penske in the No. 12 Ford, at Michigan and Indianapolis, finishing outside the top ten in both. A decade later, in 2024, Montoya returned for a single race — the Go Bowling at The Glen — driving 23XI Racing's No. 50 Toyota after accepting an invitation from team president Steve Lauletta. He qualified 34th and finished 32nd.
Montoya's NASCAR career produced two Cup Series victories, both on road courses where his car-control skills and formula racing instincts translated most directly. His 2009 Chase appearance remained the clearest example of what he could achieve when combining patience with talent. The transition from open-wheel cars to stock cars tested Montoya in ways he had not experienced in Formula One — managing traffic, aggressive short-oval racing, and the social dynamics of the garage — but his seven full-time Cup seasons and assorted part-time appearances over two decades confirmed his lasting connection to American motorsport.