MELBOURNE, Australia -- Andy Murray had already been upset by Mischa Zverev, undone by some old-school serve and volley, and Roger Federer was down 5-1 in the first set against Kei Nishikori.

As Sunday stretched from afternoon to evening, the second week of the Australian Open appeared set to take on a drastically different complexion than any in a decade.

Unlike newly-installed No. 1 Murray, though, the long-time top-ranked Federer found a way to fend off his fourth-round rival.

The sum result of back-to-back long matches on Rod Laver Arena was a quarterfinal pairing of 17th-seeded Federer against No. 50-ranked Zverev.

Five-time finalist Murray lost in a 7-5, 5-7, 6-2, 6-4 to 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.

Federer held off 2014 U.S. Open finalist Nishikori, who was cramping and needed late treatment on his back, 6-7 (4), 6-4, 6-1, 4-6, 6-3.

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 obviously very down because I wanted to go further in this event, and it wasn't to be," Murray said. "I've had tough losses in my career in the past. I've come back from them. This is a tough one. I'm sure I'll come back OK."

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.

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, 14-time major winner Rafael Nadal is the only man still in contention who has won a Grand Slam title.

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.

"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 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."

Seven-time major winner Venus Williams returned to the 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.

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.

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's fourth-round departure in 2003.

The younger Zverev brother 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.

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.