Rossi began the new season with a fifth-place finish at St. Petersburg. He scored the first win of his 2019 season at Long Beach, where he repeated his success from the previous season. Rossi’s 20-second margin of victory over Newgarden was the largest margin of victory at Long Beach since Al Unser Jr.’s 23-second margin in 1995. He dedicated the victory to his grandfather; the win came on the day Rossi learned of his death.

In 2005, after becoming IKF Grand National Champion in the 100cc Yamaha class, Auburn-born Rossi was semi-finalist in the Red Bull Formula One American Drivers search with a top 5 finish overall out of over 2,000 nationwide candidates.

In 2006 he was awarded the Skip Barber National Scholarship from Skip Barber Racing School to compete in the 2006 Skip Barber National Championship, where he finished third overall, becoming the youngest winner in Skip Barber National Championship history, at age 14.

Rossi competed in the 2009–10 GP2 Asia Series. Having competed for Ocean Racing Technology at the first Abu Dhabi round, Rossi moved to Team Meritus for the remaining rounds. Rossi made a strong impression immediately finishing fourth in his début race, from thirteenth on the grid. Rossi was only the second American to compete at GP2 level, preceded by Scott Speed who raced in Formula One with Scuderia Toro Rosso in 2006 and 2007. Rossi finished ninth in the championship standings.

Rossi competed in the Formula BMW USA series in 2007, finishing third overall in the championship, with three wins and five podiums while driving for Team Apex Racing, USA.

For 2008, Rossi returned for his second year with the two-time Formula BMW championship-winning team EuroInternational. He won the overall championship, becoming the first American Formula BMW Champion in the Americas Championship, with ten wins from the fifteen races run.

Rossi decided to move to compete in Europe in 2009. He chose to compete in the International Formula Master with Hitech Racing. After two rounds, Rossi moved over to ISR Racing for the remainder of the season. Rossi won three races over the course of the season, all coming during reverse-grid races. The wins at Brno, Spa and Imola gave Rossi the second-highest tally of victories during the 2009 season, with Fabio Leimer (seven) winning more. Coupled with Pål Varhaug’s sixth place in the final race at Imola, Rossi moved up to fourth overall in the championship, and the highest-placed rookie driver.

In 2010, Rossi made the move to the new GP3 Series, competing for multiple-championship-winning team ART Grand Prix. He joined Pedro Nunes and Esteban Gutiérrez at the team, winning twice and finishing fourth in the series.

For the 2012 Formula One season, he joined Caterham F1 as a test driver alongside reserve driver Giedo van der Garde. At the Spanish round he drove Heikki Kovalainen’s car in the first practice session, becoming the first American to drive in a Formula One session (during a race weekend) since Scott Speed at the 2007 European Grand Prix. In 2013, he drove for Caterham in the first practice session of the Canadian Grand Prix and at Silverstone in July for the young driver test. Later in the season, he again participated in the first practice session at the United States Grand Prix, his home race. In 2014, he drove the Caterham in the first practice session of the Canadian Grand Prix. Rossi departed Caterham following the departure of Tony Fernandes and the entrance of new Swiss and Middle Eastern investors in July 2014.

After his stint at the Formula Renault 3.5, Rossi made his GP2 Series debut in the Bahrain round in 2013 after replacing Chinese driver Ma Qinghua, he finished 3rd in his debut race. On July 16, 2014, Rossi announced he had departed Caterham’s GP2 team, and later joined Campos Racing at the Hockenheimring, replacing Kimiya Sato. He joined Racing Engineering for the 2015 season opposite British rookie Jordan King, finishing second in the championship.

In 2013, Rossi made his debut at the 24 Hours of Le Mans, driving for Greaves Motorsport in a Zytek Z11SN. He was signed as a replacement for Christian Zugel, who was prevented from participating by family and business matters. He and co-drivers Eric Lux and Tom Kimber-Smith finished 23rd overall.

Rossi competed in the 2014 24 Hours of Daytona for the DeltaWing team, joining full-time drivers Andy Meyrick and Katherine Legge, along with eventual 2014 Indy Lights champion Gabby Chaves.

Despite signing for Andretti Autosport in the IndyCar Series, Rossi returned as a reserve driver for the reformed Manor Racing for the 2016 season. After Rio Haryanto lost his ride at Manor following the German Grand Prix, Rossi was offered the opportunity to take his place as a full-time driver; however, he declined the offer, stating: “My management and I are in constant communications with Manor and we knew there might be an opportunity to race for the last half of the 2016 season. We gave it careful thought but declined the race seat due to my IndyCar contract.” On October 3, 2016, Rossi confirmed he would give up his reserve driver role at Manor following the 2016 season to focus on the IndyCar Series full-time.

Rossi’s 2016 Indianapolis 500 win earned him a nomination at the 2016 ESPY Awards for Best Driver. He attended the awards ceremony on July 13, though the award went to NASCAR’s 2015 Sprint Cup Series champion, Kyle Busch.

On December 7, 2017, Andretti Autosport announced plans for Rossi to swap car numbers with teammate Marco Andretti for the 2018 season. Rossi moved to the No. 27 team while Andretti took over the Herta-partnered No. 98.

Rossi is a Protestant Christian. He cites his two most important life influences as God and his parents, adding, “I believe there’s always a greater plan. I feel that driving race cars and being involved in Formula One and motorsports is my opportunity to share my beliefs.” Rossi describes having his faith while growing up as “something that was hugely important to me. That carried all the way through my entire childhood. I was very fortunate to be a product of a Christian family with my mom and dad and grandmother.” He was a speaker at the Fellowship of Christian Athletes’ “Nights of Champions” program in 2017. When asked in mid-2019 about his status at Andretti Autosport beyond the end of that season, Rossi replied that his career path was “in God’s hands.”

In March 2017, Rossi was a guest on an episode of Harry Connick Jr.’s eponymous talk show, Harry. He has appeared on The Rich Eisen Show on two occasions, in July 2016 after winning the Indianapolis 500 and again in January 2018.

On December 7, 2018, Rossi announced that he would be joining Acura Team Penske for both the 24 Hours of Daytona and the 12 Hours of Sebring in the 2019 IMSA WeatherTech SportsCar Championship. Rossi replaced fellow IndyCar driver Graham Rahal after Rahal was unable to get an adequate seat fitting to optimize his performance. Rossi teamed with fellow IndyCar Series driver Hélio Castroneves and sports car driver Ricky Taylor to finish third overall and in class at Daytona. The second half of the race was marred by non-stop rain, with Rossi conceding that the team’s rivals were slightly stronger than them in wet conditions.

Rossi’s 2018 season began with a controversial third-place finish at the Grand Prix of St. Petersburg. Rossi was running in second on the final restart and attempted to pass leader Robert Wickens in the first turn, but got loose and made contact with Wickens, who in turn retired from the race. Rossi argued that while he “[felt] bad” about the contact, he also believed Wickens’ defense of the lead forced him into the marbles, causing his car to get loose. Wickens, however, said he “expected more” from Rossi, and proceeded to call his move “desperate.” Rossi’s driving was further criticized by NBC Sports’ Jerry Bonkowski, who opined that he “ruined what was a near-perfect day — make that weekend — for another driver.” Ironically, Rossi would again battle with Wickens in the closing stages of the following race at Phoenix, securing another third-place finish behind race winner Josef Newgarden and Wickens. After the podium celebration, both Wickens and Rossi made light of the St. Petersburg clash; Rossi stated that Wickens “should definitely have two podiums right now,” to which the Canadian jokingly replied, “About time you said it!” The following week, Rossi qualified on pole position for the Grand Prix of Long Beach. He converted the pole position into his third career win, leading race runner-up and 2014 IndyCar Series champion Will Power to call Rossi “a standout of the field right now in every respect.”

Rossi competed in his first ever Baja 1000 in 2018, driving with Jeff Proctor in the No. 709 Honda Ridgeline, becoming the fifth Indianapolis 500 winner to participate in the race. Rossi explained that he was eager to try a different racing series, saying, “It’s just one of those iconic races. There’s a Honda connection, so [when offered the ride] I just figured, ‘Why not?’ I’m pretty excited about it. It’s something new, something different. I’m looking forward to the experience.” Rossi nearly collided with a spectator’s car that was travelling the wrong way on the course around 33 miles into the race. His team placed second in their class in the final results.

Rossi appeared on the 30th season of CBS’ The Amazing Race with fellow IndyCar driver Conor Daly as his teammate. The pair won the fourth leg of the race, though they were eventually eliminated, finishing in fourth place. On April 19, 2018, he appeared on the season four premiere of CNBC’s Jay Leno’s Garage alongside Tanner Foust.

At the 2019 Indianapolis 500, Rossi was in contention for the win before encountering a fuel pump problem in the pits on lap 137. The delay resulted in a 23-second pit stop, which likely would have taken him out of contention had Marcus Ericsson not spun entering the pit lane, forcing a caution flag. On the ensuing restart, Rossi fell from fifth to sixth place, while also being seventh in line as Oriol Servià, a lapped car, was in front of him. Rossi was then held up and blocked by Servia (he would later call his actions “unacceptable” and “one of the most disrespectful things I’ve ever seen in a racecar”), eventually shaking his fist at the Spanish driver as he finally passed him. Rossi eventually recovered to pass Simon Pagenaud for the lead and seemed to have the advantage as Pagenaud was in danger of not being able to make it to the end of the race on fuel, but a late caution nullified that advantage. Rossi’s Honda lacked the horsepower of Pagenaud’s Chevrolet, which was ultimately the deciding factor as he finished the race in second behind Pagenaud.

Rossi returned to the Baja 1000 in 2019. Rossi and Proctor’s truck was leading when Rossi rolled over the vehicle. The truck was able to continue for about 100 miles after the crash but eventually retired due to mechanical problems.

On August 15, 2019, Rossi announced plans to make his debut in the Bathurst 1000 in October, competing with fellow IndyCar Series driver James Hinchcliffe as a wildcard entry for Walkinshaw Andretti United, a partnership between Andretti Autosport and United Autosports. The pair started the race on the back row of the grid in 25th, finishing 19th before being promoted to 18th after a penalty demoted DJR Team Penske’s Fabian Coulthard from sixth to 21st.

In 2020, Rossi used his some of his helmets to raise awareness for charitable causes. After his Bathurst 1000 debut, Rossi auctioned off his helmet, donating the proceeds to Wires Wildlife Rescue in aid of the Australian bushfires. His Indianapolis 500 helmet in August was designed by TAG Heuer to honor frontline workers and heroes in the midst of the COVID-19 pandemic.