Andy Murray won't be breaking his Australian Open title drought this year after a stunning fourth-round loss to 50th-ranked Mischa Zverev.

The five-time Australian Open finalist was unsettled by the left-handed serve-and-volleyer in a 7-5, 5-7, 6-2, 6-4 upset loss Sunday that seriously changes the tournament landscape in the second week.

Murray's exit follows the second-round departure of six-time defending champion Novak 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 haven't reached the Australian Open quarterfinals, and the first time at a Grand Slam since the French Open in 2004.

"Right now I'm down," Murray said. "But I've had tough losses before and come back from them."

The absence of Djokovic and Murray from the quarterfinals — the first time since 2007 that at least one of them hasn't reached the last eight at a major — opens up opportunities.

Zverev will play a quarterfinal against the winner of Sunday's later match between 17-time Grand Slam champion Roger Federer, who is returning from injury, and No. 5 Kei Nishikori, who reached the U.S. Open final in 2014 but has never won a Grand Slam.

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.

On the other half of the draw, Rafael Nadal is the only man still in contention who has won a Grand Slam title. The 30-year-old Spaniard has 14 — but none since the 2014 French Open.

Zverev attacked Murray, unsettling his natural baseline game, and won 65 of 118 points at the net.

The 29-year-old German made some stunning, lunging volleys on clutch points, but for him it was all a blur.

"Honestly, I don't know, 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 got the closest look at Zverev's best match to date, and couldn't do a lot to counter it.

"It's the shots he was coming up with when he did come forward." Murray said. "I mean, he came up with some great pickups, you know, reflex volleys especially at the end when it was tight.

"He served very well when he needed to ... he deserved to win because he played great when he was down, and also in the important moments."

In women's fourth-round matches, seven-time major winner Venus Williams returned to the Australian Open quarterfinals for the ninth time with a 6-3, 7-5 win over No. 181-ranked Mona Barthel.

She will next play No. 24-seeded Anastasia Pavlyuchenkova, who beat No. 8 Svetlana Kuznetsova 6-3, 6-3.

French Open champion Garbine Muguruza reached the quarterfinals in Australia for the first time, beating Sorana Cirstea 6-2, 6-3.

"When you win one (major), you have that self-confidence and that belief in yourself that you can do it again."

Murray had reached the quarterfinals or better on his previous seven trips to Melbourne Park — losing the finals in 2010 to Federer and in '11, '13, '15 and '16 to Djokovic.

Murray had not lost to a player ranked as low at a major in a decade since his loss to No. 51 Juan Ignacio Chela at Melbourne Park in 2006. It was also the earliest exit by a top-seeded player at the Australian Open since Lleyton Hewitt's fourth-round departure in 2003.

And this is not even the Zverev brother tipped to go this far at the Australian Open. The 19-year-old Alexander Zverev, widely touted as a potential major winner, led by two sets to one before losing to Nadal in the third round.

The younger Zverev was in the crowd at Rod Laver, where the bulk of fans were pulling heavily for Murray as the fourth set began, shouting "Come on Andy!" after nearly every point.

Murray was agitated right from the start, hitting into the net early on and screaming loudly as glanced at his players' box.

With Zverev serving at 2-3, Murray also clubbed a backhand off his frame that went deep into the crowd and stood motionless on the court.

Serving at 4-3, Zverev hit two easy shots into the net, including a routine-looking overhead from Murray's defensive lob, drawing gasps from the crowd.

But as he held on for what turned out to be the biggest win of the year, he gained support with daring play and frequent trips to the net.

After closing it out on his first match point, he walked calmly to the net and clasped his hands together in front of his chest, almost in relief.