Quan first rose to fame as a 12-year-old when he played Indiana Jones's sidekick Short Round in the 1984 sequel Temple of Doom.
He subsequently played Data in The Goonies, before dropping out of the acting business in the 1990s when career opportunities dried up.
But he made his triumphant big screen return in 2022 as the multiple multiversal variants of Waymond Wang in Everything Everywhere All at Once, for which he won Best Supporting Actor at Tuesday's awards ceremony.
In the film, Waymond is the devoted husband to Michelle Yeoh's protagonist, as well as her guide to the multiverse and her destiny as a hero as Alpha-Waymond.
He beat out the likes of Brad Pitt, Brendan Gleeson and Eddie Redmayne to win the Golden Globe with his first nomination.
Taking to the stage, he said: "I was raised to never forget where I came from and to always remember who gave me my first opportunity. I am so happy to see Steven Spielberg here tonight. Steven, thank you.
"When I started my career as a child actor in Indiana Jones and the Temple of Doom, I felt so very lucky to have been chosen. As I grew older, I started to wonder if that was it... if that was just luck.
"For so many years, I was afraid I had nothing more to offer, that no matter what I did, I would never surpass what I achieved as a kid.
"Thankfully, more than 30 years later, two guys thought of me. They remembered that kid, and they gave me an opportunity to try again.
"Everything that has happened since has been unbelievable. [Everything Everywhere directors] Dan Kwan, Daniel Scheinert, thank you so much for helping me find my answer. You have given me more than I could have ever hoped."
Emotional viewers watching the Globes were quick to praise Quan for his raw and honest speech about his career.
This is everything. I’m in tears watching this. A reminder that you ALWAYS have something to give and share with the world. Congrats Ke Huy Quan! ❤️pic.twitter.com/Cz3g6kmZNF
— Andrew Phung (@andrewphung) January 11, 2023
— Ema Sasic (@ema_sasic) January 11, 2023
Ke Huy Quan’s acceptance speech for winning his first Golden Globe. I’m in tears, man. pic.twitter.com/wKVF5YTlka
— Metalcore Nerds (@MetalcoreNerds) January 11, 2023
Quan's career comeback is set to continue apace in the coming years, starting with a role in the cast of Marvel TV show Loki for its second season.
He will also appear on Disney+ in the TV adaptation of the graphic novel American Born Chinese, which consists of three separate but ultimately interlinked stories.
Quan's co-star Michelle Yeoh also bagged the award for Best Actress - Musical or Comedy at the Golden Globes, capping off a great night for Everything Everywhere All at Once.
The film was also nominated for Best Motion Picture - Musical or Comedy, but lost out to The Banshees of Inisherin.
Watch: Trailer for Everything Everywhere All at Once