After karting, Karam competed in the 2010 season of the U.S. F2000 National Championship for Andretti Autosport. Karam won nine of the twelve races and the pole in all but one race and dominated the championship. For winning the championship, as a part of the Road to Indy program and the Mazdaspeed development ladder, Karam won a prize package valued at US$350,000 that allowed him to compete in the Star Mazda Championship in 2011, again with Andretti Autosport. Karam won back-to-back oval races at the Milwaukee Mile and Iowa Speedway and finished fifth in points, winning rookie of the year honors. He returned to the team and series in 2012 and improved to third in points with three race wins.
In 2013 he moved up the Road to Indy ladder to the Firestone Indy Lights series with Schmidt Peterson Motorsports. Karam won the Indy Lights title that year, becoming the eighth rookie to win the series championship.
Karam was signed by Chip Ganassi Racing to compete in some endurance sportscar races of the United SportsCar Championship in 2014. He ran in the 24 Hours of Daytona, driving the No. 01 car alongside Scott Pruett, Memo Rojas and Jamie McMurray, and entered the 12 Hours of Sebring in the No. 02 next to IndyCar drivers Scott Dixon and Tony Kanaan.
Ganassi secured Karam a seat in the 2014 Indianapolis 500 with Dreyer & Reinbold Racing, which had not run an IndyCar race since the previous "500". Karam qualified 31st but drove an outstanding race to finish ninth, the second highest-finishing rookie.
Karam appeared in the 2015 IndyCar Series season piloting Chip Ganassi Racing's #8 Dallara. He finished 32nd in the 2015 Indianapolis 500, after a first lap incident with Takuma Sato. Karam captured his best finish at the 2015 Iowa Corn 300 at Iowa Speedway in July by finishing third and scoring his first career podium.
Karam's fast but reckless controversial style quickly alienated fellow competitors and confounded Indycar team owners. At Texas he was accused of reckless driving by fellow competitor Ed Carpenter. At Mid-Ohio speculation became rife he deliberately spun the vehicle under team orders in a gambit to manipulate the 2015 Indycar Championship. Team principals replaced him 4 occasions with relief driver Sebastián Saavedra.
In his Pennsylvania homecoming at Pocono Raceway for the 2015 ABC Supply 500 on August 23, Karam was leading with 21 laps remaining when he lost control exiting turn 1, eliminating his Chip Ganassi number 8 Dallara as it spun and crashed hard into the wall. Debris strewn from Karam's disintegrating car made contact with fellow competitor Justin Wilson's helmet, sending him into the infield wall where the safety team extracted him unconscious and unresponsive, necessitating an emergency medevac to Lehigh Valley Hospital in Allentown where Wilson lay comatose, in critical condition. Wilson died on August 24, 2015.
Karam was again replaced for the 2015 season finale at Sonoma, by Sebastián Saavedra. Karam finished the 2015 IndyCar season 20th in points, bested by rival Gabby Chaves for 2015 rookie of the year honors. Replaced for the 2016 season, Karam's seat in the Chip Ganassi stable piloting the number 8 Dallara was secured by Max Chilton.
A one race agreement for 2016, Dryer & Reinbold signed Karam for the Indianapolis 500, initially with Havoline and Gas Monkey Energy as sponsors. Steadily improving from his 23rd qualifying slot on grid, into the top 10, yet again Karam crashed the car on lap 94, attempting a high-side pass on Townsend Bell into Turn One.
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