Kyrgios was trailing Dutchman Botic van de Zandschulp 7-6 (9-7) 3-0 in Indian Wells when he quit the first-round encounter with a right wrist injury.
Playing on an injury-protected ranking after being sidelined for almost three years, Kyrgios had held a set point in the first-set tiebreaker.
But it was all downhill after dropping the set.
The one-time world No.13 was visibly upset speaking to a tournament trainer, knowing his night - and possibly his singles career - was over.
The 29-year-old wiped away tears before walking over to van de Zandschulp and conceding the match.
"I wasn't too confident that I was going to be able to play today," Kyrgios said.
"Two days ago in practice, I had to stop my practice because I felt pain in my wrist, but I felt like it was OK to take to the court."
If Kyrgios had won, he would have played the legendary Novak Djokovic in the second round.
Instead his withdrawal casts further doubt on his career after the 2022 Wimbledon finalist made a lame first-round exit from the Australian Open in January.
Kyrgios conceded after that Melbourne Park exit that he may have played his last-ever singles match at his home slam.
It was his first appearance at a major since making the 2022 US Open quarter-finals, before then requiring wrist and knee surgeries.
In all reality, the controversial Canberran's singles career may finished, full stop.
Languishing outside the world's top 1000, Kyrgios can continue playing on an injury-protected ranking throughout 2025.
But if he fails to win matches - and his last victory came two and a half years ago - Kyrgios will need to rely on wildcard entries to play on the ATP Tour.
He conceded in November of 2023 that "the stars have to align a little bit" to make a successful comeback.
Those words now seem prophetic, with the mercurial talent being urged to pursue a doubles career.
He won the Australian Open doubles crown with Thanasi Kokkinakis in 2022 and the team format appears the enigmatic showman's best path to capturing the attention he so craves.
Should this be the end of his singles career, Kyrgios will go down as arguably the most unfulfilled talent in men's tennis history.
His lone grand slam final appearance came after receiving a walkover in the semi-finals.
Once described by John McEnroe as the most prodigious talent in more than 30 years, Kyrgios never cracked the world's top 10 or helped Australia to a Davis Cup final, let alone win one.
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