Vandeweghe had never been past the third round at the season-opening Grand Slam, and lost in the first round here last year. But she pounded Kerber with a powerful forehand, clubbing 13 of her 30 winners from that wing.
“First time I've ever beaten a world No. 1,” Vandeweghe said when asked to rate the win in terms of career highlights, “especially at a Grand Slam — it's pretty high.”
Kerber saved a match point in the first round last year before winning her first major title, beating Serena Williams in the final. She replaced Williams atop the rankings after winning the U.S. Open. Now Williams can regain the top spot — if she wins the title here.
Murray lost the final here to six-time champion Novak Djokovic last year, but finished 2016 at No. 1 after a strong finish to the season that included titles at Wimbledon, the Olympics and the ATP Finals.
He was undone by some old-school serve and volley from Zverev, who played the match of his life. He'll now meet 17-time major winner Federer in the quarterfinals.
In between the upsets was pretty rocky too. Federer was down 5-1 in the first set against Kei Nishikori but found a way to fend off the 2014 U.S. Open finalist, who was cramping and needed late treatment on his back, 6-7 (4), 6-4, 6-1, 4-6, 6-3.
It was Federer's 200th career win over a top 10 player.
He was ecstatic. “It was about staying with him. Almost going down 6-0, I thought, `It's not going to get any worse from there,’” said Federer, on the comeback from six months on the sidelines to repair his injured left knee. “Huge win for me in my career.”
For Murray, the overwhelming feeling was painful.
“Right now I'm obviously very down because I wanted to go further in this event,” Murray said. “I've had tough losses in my career in the past. I've come back from them. This is a tough one.”
Murray's exit follows the second-round departure of Djokovic, beaten in the second round by No. 117-ranked wild-card entry Denis Istomin.
It's the first time since 2002 that the top two seeds in the men's draw haven't reached the Australian Open quarterfinals, and the first time at a Grand Slam since the French Open in 2004.
The absence of Djokovic and Murray certainly opens up it up for others.
U.S. Open champion Stan Wawrinka, who had his major breakthrough here in 2014, is a growing contender after beating Andreas Seppi 7-6 (2), 7-6 (4), 7-6 (4). He'll play a quarterfinal against 2008 Australian Open finalist Jo-Wilfried Tsonga, who beat Dan Evans 6-7 (4), 6-2, 6-4, 6-4.
In the bottom half of the draw, 14-time major winner Rafael Nadal is the only man still in contention who has won a Grand Slam title.
The top half of the women's draw is open too. Venus Williams returned to the quarterfinals for the ninth time with a 6-3, 7-5 win over No. 181-ranked Mona Barthel.
The seven-time major winner next plays No. 24-seeded Anastasia Pavlyuchenkova, who beat No. 8 Svetlana Kuznetsova 6-3, 6-3.
French Open champion Garbine Muguruza beat Sorana Cirstea 6-2, 6-3 and will next play Vandeweghe — they're both in the quarterfinals at Melbourne Park for the first time.
Kerber's loss continued a poor run since she won the U.S. Open in September. She's played seven tournaments without winning a title, only reached one final, and was 5-7 against top 50 players.
The bigger upset of the day, then, was produced by Zverev, the older and apparently lesser-talented brother of Alexander who had never gone past the third round of a major and was appearing at only his third Grand Slam in six years.
Zverev attacked Murray, unsettling his natural baseline game, and won 65 of 118 points at the net.
He made some stunning, lunging volleys on clutch points, but for him it was all a blur.
“It was like I was in a little coma, I just served and volleyed my way through,” Zverev said. “Honestly there were a few points where I don't know how I pulled it off.”
Murray had reached the quarterfinals or better on his previous seven trips to Australia but never won the title — losing finals in 2010 to Federer and in `11, `13, `15 and `16 to Djokovic.
He had not lost to a player ranked as lowly as Zverev at a major since his loss to No. 51 Juan Ignacio Chela here in 2006. It was also the earliest exit by a top-seeded player at the Australian Open since Lleyton Hewitt in 2003.