De Minaur's watershed win also raised concerns about Djokovic's ability to win an unprecedented 11th Australian Open crown this month after the Serb was treated for an ongoing wrist injury throughout his uncharacteristically error-riddled display.
While Djokovic struggled, de Minaur was on fire from the outset of Wednesday night's match, winning 6-4 6-4 in 93 minutes to give Australia a 1-0 lead in the best-of-three-match quarter-final tie.
Ajla Tomljanovic secured victory for Australia and a spot in the semi-finals with a 6-1 6-1 win over world No.184 Natalija Stevanovic in a 64-minute masterclass.
The higher-ranked Olga Danilovic was slated to play the women's singles for Serbia, but pulled out due to fatigue.
Australia wrapped up a 3-0 tie win when Matt Ebden and Storm Hunter combined to win the mixed doubles 6-3 6-3, with the host nation to take on either Greece or Germany in the semi-finals.
Although de Minaur defeated Rafael Nadal at last year's United Cup, the win over Djokovic is even more significant, given the 36-year-old is still at the peak of his powers after winning three of the four slams in 2023.
It also represents de Minaur's maiden win over a world No.1.
AUSTRALIA RISES AS ONE 🫶🇦🇺— United Cup (@UnitedCupTennis) This is your moment, @alexdeminaur! #UnitedCup pic.twitter.com/UiPoh84EzGJanuary 3, 2024
"It's extremely special. Novak is an unbelievable competitor," de Minaur said after breaking the super Serb's 43-match, six-year winning streak in Australia.
"It feels surreal, it feels amazing. I'm happy to do it here in Perth and Australia."
Djokovic entered the match under an injury cloud after damaging his wrist while practising on Tuesday morning.
The 24-time grand slam champion said the injury affected him during Wednesday night's match, but he hopes it won't impact his Australian Open campaign.
"It did have quite an impact (tonight), particularly on the forehand and serve," Djokovic said.
"Again, I don't want to be spending too much time talking about it and taking away credit from de Minaur.Â
"I mean, he was just very solid, as he always is. Congrats to him, to the Australian team."
De Minaur was pummelled 6-2 6-1 6-2 by Djokovic in the fourth round of the Australian Open last year, but it was a different story in Wednesday night's re-match.Â
The 24-year-old's frenetic speed and amazing agility continually frustrated Djokovic, who committed 31 unforced errors for the match as he battled wrist pain.
Djokovic received treatment after being broken in the ninth game of the first set, but it did little to stem the de Minaur onslaught.
The Australian secured his second break of the match in the seventh game of the second set when Djokovic double faulted.
De Minaur had three match points at 40-0 and 5-4 up, but he blew each one, including a nervy double fault.
But he earned a fourth match point, and secured the win when Djokovic sent a backhand long.
De Minaur has spoken about his desire to be known as more than just a player who can move "side to side" well, and the use of his backhand slice during the United Cup has been a big weapon.
His powerful winners have also been a highlight.Â
"It comes from a lot of people not believing in me," de Minaur said of his motivation to bring his new weapons to the fore.Â
"I'm just here to prove a lot of people wrong, trying to get better.
"Ultimately I'm never going to be the biggest or strongest guy, so I've got to adapt.Â
"I've got to show that I've got variety in my game and I've got different styles of playing tennis.
"I'm glad I was able to bring this level today."
