Appearing in the last 16 at Melbourne Park for the first time, Vandeweghe rose to the occasion in magnificent fashion, reeling off the final five games to close out a 6-2, 6-3 victory.
"I believe this is my first No.1 win, so I'll take that," said Vandeweghe. "I was feeling bad out there but you've just got to keep at it and keep going. I had to trust my game to beat her and I did."
Vandeweghe made a mockery of her weary limbs, a spectacular display of attacking tennis producing six aces and 24 other winners in little over an hour.
After an even start, Vandeweghe fired a backhand crosscourt to claim the first break, before repeating the trick to wrap up the set. This stung the World No.1 into life, breaking Vandeweghe to open the second set. There was to be no comeback, though.
Capitalizing on a series of uncharacteristic Kerber errors, the American leant on her forehand to draw level at 3-3, before a big backhand gave her the opportunity to serve for the match. By this point Kerber was rapidly running out of ideas, sending a return beyond the baseline to surrender her crown.
? #7TENNIS ? (@7tennis) January 22, 2017
Vandeweghe, who celebrated her biggest career victory in typically laid-back fashion, moves on to face No.7 seed Garbiñe Muguruza in the quarterfinals.
"Last year I came here and didn't even win a match and here I am now," Vandeweghe added. "It's confidence having a full off-season with no injuries. I set a goal for this tournament to make the quarterfinals."
The result means that for the first time in the Open Era the Australian Open has lost both top seeds and both defending champions before the quarterfinals, following shock defeats for Novak Djokovic, and Andy Murray earlier on Sunday.
Kerber struggled to find come close to the counterpunching brilliance of 12 months ago and, if Serena Williams lifts the title, she could now leave Australia without the No.1 ranking as well as the Daphne Akhurst Trophy.
"I'm always going into matches with confidence. It's the fourth round, so every round is not easy," Kerber said. "So I'm not looking about the rankings of my opponents. I'm going out there to play good tennis, trying to play my best.
"I was trying tonight, as well, everything. But, yeah, I missed a lot and I make a lot of unforced errors. So this was not my normal game. I think she had, for sure, a good day. But, yeah, I can just say like how I was feeling. Yeah, I make a lot of mistakes. I think that was not my game I play normally."