World number one Andy Murray vowed to return as strong as ever after his bid for a maiden Australian Open title was brought to a stunning end by German Mischa Zverev on Sunday.

The three-time grand slam champion struggled to handle the world No. 50's remarkable play at the net, slumping to a 7-5 5-7 6-2 6-4 defeat at Melbourne Park on Sunday.

The shock result leaves the men's draw wide open after defending champion Novak Djokovic was earlier eliminated in the second round.

It is the first time since 2004 that the top two men's seeds have failed to reach the quarterfinals of a grand slam, and the first time this has happened at Melbourne Park since 2002.

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Murray has reached the final five times on the blue hardcourts at Melbourne Park and lost every one, four to the man who preceded him as world number one, Novak Djokovic.

With the reigning champion having made an even earlier departure from the tournament in the second round, top seed Murray was considered to have had his best chance to finally bury his Melbourne hoodoo.

The 29-year-old respectfully disagreed.

"Did I miss an opportunity?" he said. "I don't know. I mean, every year you come is a different chance.

"But you've got Roger (Federer) plus three guys that are pretty much in the top 10 in the world in my half of the draw. There's certainly no guarantees, even if I got through today's match, that I would have gone further.

"It's disappointing to lose (but) I don't feel like this is any more of an opportunity than other years."

Murray had every right to be confident when he arrived at Melbourne Park as the top seed at a grand slam for the first time after winning 28 of his previous 29 matches.

"I'm obviously down about it," said the Wimbledon and Olympic champion.

"It's just tennis. I mean, I had great success for a number of months. Obviously in the biggest events you want to do your best. Obviously that's not been the case here. You know, it happens."

Murray first came across Zverev when they were both Juniors and had no reason to think the 50th ranked serve-volley exponent would return to end his run of consecutive Melbourne Park quarter-final appearances at eight.

Although Murray paid full tribute to Zverev's extraordinary performance, there was no escaping that his was the earliest exit from the tournament for a top seed since Lleyton Hewitt in 2003.

"I've had tough losses in my career in the past. I've come back from them," said Murray.

"This is a tough one. I'm sure I'll come back okay from it. But right now I'm obviously very down because I wanted to go further in this event, and it wasn't to be.

"Credit to him. He came up with great, great shots and played a really, really good match. You know, you always finish matches you lose with things you maybe could have done a bit better, but he played some really good stuff."

'BEST MATCH OF MY LIFE'

Zverev, who will face four-time Open champion Roger Federer in the quarter-finals, struggled to find the words to describe his performance.

"Definitely the best match of my life, not only because it was a best-of-five set match (and) it was at a slam," Zverev said.

"I don't know. It was just incredible. I believed in myself. I believed in my game.

"I believed that playing serve and volley against him and slicing a lot, trying to destroy his rhythm was going to work, which it did in the end."

Zverev's younger brother Alexander was considered by far the most likely of the pair to make a deep run at the Open before his agonising five-set loss to Rafael Nadal on Saturday.

The teenage prodigy was on hand at Rod Laver Arena to cheer on his older sibling, with Zverev saying the family support helped him to stay calm.

"My mum was always smiling. That helps," he said.

"My dad's focused. Everybody else was just chilling. I feel like there's a good atmosphere going on, which keeps me entertained and focused on the court."

Zverev's road to the Open included a memorable encounter with Nick Kyrgios at the Shanghai Masters in October, which led to the firebrand Australian being slapped with an eight-week ban for tanking.

The left-hander entered this year's Open having made it past the first round just once in five previous appearances.

But it certainly didn't show, with three-time grand slam champion Murray struggling to handle Zverev's remarkable play at the net, struggling with his second serve and growing increasingly frustrated by his seeming inability to read the German's play.

With an opportunity to take a 5-3 lead in the fourth set, Zverev looked like nerves may get the better of him, hitting a simple forehand smash into the net.

But he quickly regrouped, playing a series of remarkable shots at the net to pull off one of the biggest upsets in Open history.

"Honestly, there were a few points where I don't know how I pulled them off," Zverev said.

Commentating for the Seven Network, former world No.1 Jim Courier summed up the mood at Melbourne Park.

"If you'd told me at the beginning of the tournament there would be a Zverev in the fourth round challenging a top player, I would have been absolutely right on board with you," he said.

"If you'd have said it was Mischa, you'd have had me. This is a genuine surprise."

FEDERER TRIUMPHS OVER NISHIKORI

Federer's march towards a first grand slam title in five years continued with a come-from-behind five-set win over Kei Nishikori.

The world No.17 warmed into the contest and overcame the hard-running Japanese with a 6-7 (4-7) 6-4 6-1 4-6 6-3 win on Sunday night in three hours and 24 minutes.

Nishikori was hampered by a hip problem during the fifth set and required court- side treatment.

Federer showed his displeasure at the delay, throwing a drink bottle during the break, but remained calm on the court.

The scoreline flattered Nishikori, who lost the winners count 83-42.

"He played his heart out ... he was hanging tough and playing really well on the big points," Federer said.

"This is a huge win for me in my career."

The absence of the top two seeds has increased hopes the Swiss champion will add to his collection of 17 major titles this month in Melbourne.

Against Tom Berdych in the third round Federer was irrepressible from the get-go, but on Sunday night he took a little longer to hit full stride.

Federer didn't face a break point all night against the Czech world No.10 but on Sunday he gave away eight in his opening two service games, falling 4-0 behind.

The veteran recovered to win four games in a row in front of an energised crowd, ensuring a tiebreak.

Federer was cruelled in the tiebreak when two lets were called on points he would have won, allowing Nishikori to charge on.

A set down, the 35-year-old's imperious serving game returned.

Combined with an aggressive approach to returning Nishikori - he hit nine clean winners off the world No.5's serve - Federer turned the tables.

The solitary break of the second set put Federer back on terms. He was in control after claiming the third set in 26 minutes.

Nishikori was playing under duress, showing as much when he uncharacteristically threw his racquet.

From his despair he found a way back into the match, making just three unforced errors in the fourth set to level the match.

Federer finished the stronger, perhaps due to Nishikori's troubled hip, and never looked like losing the fifth set.

The win was Federer's 200th against top-10 opposition, a record.

It also ended a four-year drought in five-set matches against a top 10 opponent.

TSONGA, WAWRINKA THROUGH TO QUARTERS

Jo-Wilfried Tsonga has prevailed where seeds Marin Cilic and Bernard Tomic failed, knocking out insurgent Brit Dan Evans.

Tsonga reached the last eight at Melbourne Park for the first time in four years with his 6-7 (4-7) 6-2 6-4 6-4 win over two hours and 53 minutes on Sunday night.

Tsonga cracked 59 winners and kept his unforced errors to just six a set after losing the opening set in a tiebreak.

His serve was a major weapon, launching 17 aces and peaking at 221km/h.

Such power and consistency holds the Frenchman in good stead for his quarter-final assignment against new Open favourite Stan Wawrinka.

"He's playing unbelievably and has won here. It's going to be a big challenge against Stan," Tsonga said.

Wawrinka was assisted by claiming early breaks in each set after the first, ensuring he regained control of the contest. His serve was not broken.

The victory sends the 31-year-old and 2008 finalist back to the quarter-finals for just the second time in the past seven years.

"It's always an opportunity when a guy like [Murray] lost," he said.

"For sure it's better for me if I don't have to play Andy because I have a bad record against him.

"But I'm just focusing on my game. My next game is going to be Stan. I cannot look forward. I have to be focused on this game."

Evans will need to be content with his best major performance in 16 grand slams, including qualifying efforts.

His fourth-round appearance sets a new benchmark, with plenty to be expected from the bustling 26-year-old in 2017.

The British No. 2 will hit a new career world position high of around 45 when the first rankings are released after the Open.