The Dutchman who stunned Carlos Alcaraz with a straight sets win at last year's US Open now has another huge scalp on his record as he beat 24-time Grand Slam champion Djokovic 6-2, 3-6, 6-1.
Van de Zandschulp lost in the second round of qualifying for Indian Wells, but was handed a place in the draw as players dropped out due to injury and he has certainly made the most of his second life in this tournament.
"I kept my cool during the whole match," said Van de Zandschulp. "The second set was very tough, but I started really well in the third set and broke him to turn it around.
"It's tough conditions out here and everything is struggling a bit, but I got through. Against the big guys I know I need to stay cool to have a chance."
There were gasps around Indian Wells as the crowd tried to appreciate what they had just witnessed in the desert, with an out-of-sorts Djokovic suffering another early exit at Indian Wells.
He lost against outsider Luca Nardi at Indian Wells last year and while this defeat against van de Zandschulp was not as big a shock, the manner of it will set alarm bells ringing for Djokovic.
With coach Andy Murray urging him on from the sidelines, Djokovic's first set display was alarming as he looked less than interested in the battle in a performance that offered flashbacks to the form he showed for long periods of 2024.
The fire was ignited inside Djokovic as he produced a battling display in the second set, but he faded badly after being broken early in the decider and ended up winning just one game in the third set.
His 37 unforced errors were evidence of his wayward performance as he backed that up with just 16 winners before a red-faced Djokovic made a swift exit from the court to ponder what went wrong and what might come next.
Djokovic has stated his intention to play at the Miami Open this year, but a defeat like this could force him to change his plans and he may now consider taking a break until the clay court season gets underway in Monte Carlo next month.
The wider picture must also be a concern for Djokovic and as he approaches his 38th birthday a few weeks from now, questions over his future in the sport will inevitably be raised once again.
"Yeah, hard to appreciate anything now, really. I'm disappointed that I lost, but I guess, you know, if you put things in that larger perspective, of course l've had an incredible career," said a downbeat Djokovic.
"Being consistent for so many years, obviously you have high expectations of yourself.
"You know, things are different obviously for me the last couple of years. I've been struggling to play on the desired level.
"Every now and then, I have couple good tournaments, but, you know, mostly it's really a challenge. It's a struggle for me. So it is what it is.
"You know, I guess nothing can prepare you for that moment, in a sense. You have to experience it and try to deal with it in the best possible way."
While Van de Zandschulp played some good tennis in this match, Djokovic appeared to be battling against himself for large parts of this match.
He also continually stretched out his shoulder and he will need to regroup and consider where his desire and ambition are taking him as he decides when to play next.
Djokovic came into 2025 with renewed ambitions to finish his career with a flourish, but setbacks like this will test his resolve to fight on against what may be increasingly long odds at this stage of his career.
The version of Djokovic who beat Carlos Alcaraz at the Australian Open in January would be a threat to win the game's biggest tournaments, but he is getting more and more defeats like this against Van de Zandschulp in the final chapters of his career and there may come a point where he concludes his winning days are over.