Karam grew up in Nazareth, Pennsylvania, racing go-karts at Oakland Valley Race Park in Cuddebackville, New York. In 2010 he entered the USF2000 Championship with Andretti Autosport, dominating the series by winning nine of twelve races and taking pole in all but one round, which earned him a prize package worth approximately US$350,000 as part of the Mazdaspeed development ladder.
He advanced to the Star Mazda Championship in 2011, again with Andretti Autosport, winning back-to-back oval races at the Milwaukee Mile and Iowa Speedway and claiming rookie of the year honours while finishing fifth in the championship standings. He returned to the series in 2012 and improved to third in points with three race victories.
In 2013 Karam moved to the Firestone Indy Lights series with Schmidt Peterson Motorsports and won the championship, becoming the eighth rookie to capture the title. The Indy Lights crown earned him a place on the Road to Indy's top rung and opened the door to IndyCar and sports car opportunities.
Chip Ganassi Racing secured Karam a seat in the 2014 Indianapolis 500 with Dreyer & Reinbold Racing. Starting 31st, he drove to a ninth-place finish — the second-highest-finishing rookie that year.
During the 2015 IndyCar season Karam shared the Chip Ganassi Racing No. 8 Dallara with Sebastián Saavedra. He showed strong oval pace throughout the year, topping the speed charts on the opening day of Indianapolis 500 practice before qualifying 23rd. His season-best result came at the Iowa Corn 300 at Iowa Speedway, where he finished third. At the 2015 ABC Supply 500 at Pocono Raceway, Karam was leading with 21 laps remaining when he lost control and crashed. Debris from his disintegrating car struck fellow competitor Justin Wilson's helmet, resulting in injuries from which Wilson died the following day, August 24, 2015.
Karam returned to the Indianapolis 500 on successive single-race agreements with Dreyer & Reinbold Racing in 2016, 2017, 2018, and 2019, with varying fortunes including crashes in 2016 and 2018 and mechanical failure in 2017. His best result in those appearances came in 2021, when he qualified from the final row — the eleventh row alongside Will Power and Simona de Silvestro — and finished seventh, his best Indianapolis 500 result to that point. In the 2019 season he also drove for Carlin at the Honda Indy Toronto.
Ganassi also fielded Karam in the United SportsCar Championship in 2014. At the 12 Hours of Sebring he drove the No. 02 car alongside Scott Dixon and Tony Kanaan, taking the lead in his opening stint from third place before handing off to Dixon, who was ultimately pushed off course by a back-marker, leaving the team in sixth at the finish. He returned to endurance racing in 2017 for 3GT Racing's Lexus RC F GT3 programme in the IMSA WeatherTech SportsCar Championship.
Dreyer & Reinbold Racing signed Karam for five races in the 2019 Americas Rallycross Championship. He never finished lower than second and earned a victory at Mid-Ohio Sports Car Course. In 2021 he competed in Nitro Rallycross with the same team, finishing second in the championship standings with five wins and seven podiums.
Karam made his NASCAR debut in 2021 in the Xfinity Series for Jordan Anderson Racing at the Indianapolis Motor Speedway road course. His schedule expanded to include Xfinity races at Bristol Motor Speedway and the Charlotte Motor Speedway Roval, as well as a Truck Series appearance at Martinsville Speedway. He ran part-time in the Xfinity Series for Alpha Prime Racing in 2022 and 2023, with a notable top-five finish at Road America in 2023. From 2024 onward he competed part-time across multiple Xfinity teams. He subsequently moved to the NASCAR O'Reilly Auto Parts Series driving for Joey Gase Motorsports.
Karam is of Lebanese heritage and graduated from Nazareth Area High School in 2014. He lives in Easton, Pennsylvania, with his wife Abigail, whom he married on July 16, 2021.
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