DeFrancesco was born fifteen weeks premature on January 17, 2000, to Andrew and Cathy DeFrancesco. He weighed only a pound at birth and was cared for at Toronto's Sunnybrook Health Sciences Centre until he was nursed back to health.
In 2014, DeFrancesco placed second overall in the Italian Championship and third overall in the CIK FIA European Championship. He sustained a wrist injury that year, requiring two surgeries and keeping him out of a full racing series for roughly a year. As part of his rehabilitation, Devlin attended the Carlin Academy, where he used simulators and on-track testing to prepare for FIA Formula 4-style racing.
In 2015, DeFrancesco was selected for the Generation Ganassi Driver Identification Program, a mentoring program sponsored by Chip Ganassi Racing.
Graduating from karts in 2015, DeFrancesco competed in the 2015 Ginetta Junior Championship with HHC Motorsports. He finished 23rd in the standings with 66 points.
In early 2016, DeFrancesco competed in New Zealand's Toyota Racing Series with Giles Motorsport. He finished the season tenth overall with 465 points.
DeFrancesco joined Carlin Motorsports for the 2016 MSA Formula season, taking three wins and finishing fifth in the points standings.
DeFrancesco continued his collaboration with Carlin Motorsport in the Euroformula Open and Spanish Formula 3 Championships in 2017. He ended the season as Spanish Formula 3 champion with three wins and five podiums. He also won a victory and seven podiums in the Euroformula Open championship, netting third in the championship standings.
DeFrancesco joined the FIA Formula 3 European Championship for the final two rounds of the 2017 season. He teamed up with Carlin again in 2018, competing in the opening two races. He later switched to the GP3 Series for the remainder of the 2018 season, teaming up with MP Motorsport.
Joining MP Motorsport, DeFrancesco finished the year in 21st place without scoring points.
In 2019, DeFrancesco contested the inaugural FIA F3 championship with Trident Racing. He did not score points and finished 25th. In February 2020, it was announced that DeFrancesco would rejoin Trident Racing for a second year, but he withdrew from the season due to fears of COVID-19, being immunocompromised.
DeFrancesco took part in a partial 2019/20 F3 Asian Championship with Absolute Racing, finishing seventh in the championship with three podiums.
DeFrancesco raced in the WeatherTech SportsCar Championship, joining the grid for the 2018 24 Hours of Daytona. He finished sixth on debut and returned for the ‘Petit Le Mans’ event at Road Atlanta in October, finishing ninth. In 2019, DeFrancesco returned to the Daytona 24 with JDC MotorSports. The race ended early due to heavy rainfall, placing the car in fifth place.
In 2020, DeFrancesco joined Steinbrenner Racing and Andretti Autosport to compete in the 2020 Indy Pro 2000 Championship. He scored two wins and was runner-up to Sting Ray Robb.
DeFrancesco moved to Indy Lights in 2021 in a car co-entered by Steinbrenner Racing and Andretti Autosport. With two podiums and nine top-fives, he finished sixth in the points standings.
DeFrancesco joined the IndyCar Series for the 2022 season, driving the Number 29 car entered as Andretti Steinbrenner Autosport. He had a best result of twelfth at Gateway and ranked 23rd in the driver's standings. DeFrancesco continued with the same team for the 2023 season and finished 22nd. DeFrancesco failed to secure a ride for the 2024 season and did not participate in any IndyCar races that season.
DeFrancesco returned to the series in 2025 after signing a multi-year deal to drive for Rahal Letterman Lanigan Racing. Following Mick Schumacher's signing in November 2025, DeFrancesco is out of an IndyCar ride for 2026.
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