Karam grew up in Nazareth, Pennsylvania and raced cars at Oakland Valley Race Park in Cuddebackville, New York. He has a younger sister, a swimmer. He graduated from Nazareth Area High School in 2014.
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 a number of endurance sportscar races in 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 the 12 Hours of Sebring in the No. 02, next to IndyCar drivers Scott Dixon and Tony Kanaan.
The Daytona 24 Hours was a short race for Sage, as they suffered engine troubles and dropped out early.
Taking over in hour four, Karam made his 12 Hours of Sebring debut a memorable one by taking the No. 02 car from third place to the lead in his opening lap then extending his lead through the end of his driving stint. Karam took the wheel for his second stint with the car in fourth place and proceeded to drive to the lead again before handing off to Dixon, who was then knocked off course of a back-marker, leaving them in sixth place at race end.
Back in the 01 car for Watkins Glen, teamed with Scott Pruett and Memo Rojas, things went awry quickly for the trio as first Rojas was sent hard into the wall by a slower GT car. They returned to the race several laps down, only for Pruett to suffer similar consequences when knocked into the wall by a sports prototype.
With Rojas sidelined due to nagging back injuries, Karam started for his final appearance of the season at the Brickyard Grand Prix, teamed with Pruett in the 01 car. Starting sixth, he skillfully dodged a major melee as several cars came together at the start. The 01 team remained among the leaders and lead 11 laps before collecting a second place, podium finish.
During 2016, Karam worked as test driver of the Lexus RC F GT3. He will compete at the 2017 IMSA WeatherTech SportsCar Championship.
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.
During the 2015 IndyCar Series season Karam split the driving duties for the Chip Ganassi Racing No. 8 Dallara with Sebastián Saavedra running 4 races on a limited budget. He finished 32nd in the 2015 Indianapolis 500, taking himself out of contention after a failed first lap high-side pass on Takuma Sato, in turn four. 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, after which he was accused of reckless driving by fellow competitor Ed Carpenter. At Mid-Ohio he was accused of spinning (under team orders) in an attempt to manipulate the 2015 Indycar Championship.
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.
On a one race agreement for 2016, Dryer & Reinbold signed Karam for the Indianapolis 500, initially with Havoline and Gas Monkey Garage as sponsors. Steadily improving from his 23rd qualifying slot on grid, into the top 10, yet again Karam crashed the car, attempting a high-side pass, lap 94, on Townsend Bell into Turn One.
On a successive one race agreement, again Dryer & Reinbold signed Karam for the 2017 Indianapolis 500. Having improved from his 21st qualifying slot into the top 10, Karam retired his number 24 Dallara-Chevrolet at the 275 mile juncture, with a dead battery.
** Podium (Non-win) indicates 2nd or 3rd-place finishes.
*** Top 10s (Non-podium) indicates 4th through 10th-place finishes.
As of August 2015, Karam lives in Nazareth, PA