The Serbian defending champion was sensationally knocked out in the second round of the Australian Open by Uzbekistan's Denis Istomin on Thursday, with the 117th-ranked Istomin ousting the six-time winner 7-6(10/8), 5-7, 2-6, 7-6 (7/5), 6-4 in 4hr 48min on Rod Laver Arena.
Here, Sport360 looks back at five other occasions where top-ranked players have been dumped out of the majors in the early rounds.
WIMBLEDON 2013 - FEDERER KNOCKED OUT IN ROUND TWO
Swisss star and defending champion Roger Federer was beaten 6-7 (5-7) 7-6 (7-5) 7-5 7-6 (7-5) in a four-set epic by world number 116 Sergiy Stakhovsky in the second round at SW19.
At the time, it was the 17-time Grand Slam champion's earliest exit at a major since 2003.
Two-time SW19 winner Rafael Nadal was knocked out in a Centre Couty epic by world no100 Lukas Rosol. The Czech battled and bruised his way to a famous 6-7 (9-11) 6-4 6-4 2-6 6-4 win.
FRENCH OPEN 2009 - SODERLING DOWNS NADAL
Super Swede Robin Soderling became the first man to beat Rafael Nadal at Roland Garros, dashing the Spaniard's hopes of winning a fifth title in a row. Nadal was powered off the court at the fourth-round stage as Soderling made his way through to the final, losing to Federer.
WIMBLEDON 2003 - LLEYTON HEWITT SENT PACKING IN OPENER
The Australian defending champion became only the third man in history to get knocked out in the first round of his title defence - losing to big-serving Croatian Ivo Karlovic, 6-7 (9-11) 6-4 6-4 2-6 6-4.
WIMBLEDON 2002 - SAMPRAS'S WIMBLEDON CAREER ENDS IN DEFEAT
There was to be no fairrytale ending at Wimbledon for the seven-time SW19 champion as Swiss player Bastl, the world no145 and lucky loser qualifier, beat the American in five sets on Court 18.
Arab No1 Malek Jaziri matched his best grand slam performance by reaching the third round of the Australian Open on Wednesday.
The Tunisian world No56 beat talented Kazakh teenager Alexander Bublik 6-2, 6-3, 7-5 to set up a last-32 clash with Germany’s Mischa Zverev, who saved a match point en route to his 6-7(4), 6-7(4), 6-4, 7-6(7), 9-7 over No19 seed John Isner of the US.
Jaziri’s best major result also came in Melbourne when he reached the third round in 2015 before falling to Nick Kyrgios.
“It was not an easy match, the guy was motivated, he had nothing to lose, was serving very well,” Jaziri told Sport360 of Bublik, who had upset No16 seed Lucas Pouille in the opening round on Monday.
“I played well, I changed a lot the rhythm of the game, I was playing with a lot of variation.
“It was windy today and it wasn’t easy to play but the first two sets I was there in all the points, I was aggressive from the start.
“He’s a young guy, you have to be there since the beginning to put an impression and I felt like I did that well. In the third set I was down 3-5 but I came back after losing my concentration briefly. I’m happy with the win, it was very important for me.”
Jaziri is 2-0 at the Challenger level against Zverev but they haven’t faced off since 2014. Zverev, the older brother of the higher-ranked Sascha, was ranked 171 this time last year but has made a solid march up the standings and is up to No50.
“I think it won’t be an easy match. He’s playing different, more serve-and-volley, more aggressive in the game. He showed a lot of good results in the last few months. He’s a dangerous player,” said Jaziri of Mischa Zverev, adding that joining forces with his new coach Christophe Freyss has been great so far.
“I’ve been working hard, I feel like I have more experience at this level and I’m working with a coach who has a lot of experience as well. So it’s important for the next step for me and hopefully I will make it.”
11 – Consecutive quarter-finals for Federer (2004-14), the Open era record for QF streak at the Aussie Open. Djokovic has made the last nine quarter-finals down under (2008-16).
11 – Consecutive semi-finals for Federer (2004-14), the Open era record.
3 – Consecutive finals played by Mats Wilander (1983-85), Ivan Lendl (1989-91) and Djokovic (2011-13) – the Open era record. Swedish great Wilander featured in four consecutive Finals (1983-88 – incl. skipped events); the Australian Open was not held in 1986 due to the Open changing dates from December to January and Wilander skipped the event in 1987.
3 – Consecutive titles won by Djokovic (2011-2013), the Open era record. At the 2017 Open, Djokovic will bid for a second triple down under. American great Andre Agassi won three successive titles (2000-03; incl. skipped events). Agassi withdrew from the event in 2002 (wrist injury).
26 – Consecutive match wins for Agassi in Australia (2000-04; missed 2002), the Open era record. Djokovic registered a 25-match win Streak Down Under from 2011-2014.
2 – Players in the Open era have won the Austrailian Open without dropping a set:
1971 – Ken Rosewall (5 matches)
2007 – Federer (7 matches – the only man to achieve this feat on a hard court)
5 – Players have won the Aus Open on their tournament debut in the Open era: Jimmy Connors (1974), Roscoe Tanner (1977 – Jan), Vitas Gerulaitis (1977 – Dec), Johan Kriek (1981), Andre Agassi (1995)
48 – Games lost by Agassi en route to winning the Australian Open in 2003, the Open era record for least games lost while winning the tournament; the American won 71.6% of games (121-48) in 2003 – the best games winning % at a single tournament in Melbourne.
20 – Consecutive appearances by Aussie legend Lleyton Hewitt (1997-2016) at his home Slam, the Open era record for most appearances at the Australian Open.
12 – Quarter-final appearances for Federer (2004-14, 16), the Open era record.
Federer is unbeaten in Aus Open quarter-finals (12-0) – only two men in the Open era hold a 100% winning record in QF matches at a single major (with atleast 10 quarter-finals)
Federer – 12/0 (Australian Open) 2004-14, 2016
Djokovic – 10/0 (US Open) – active streak 2007-16
12 – Semi-final appearances for Federer (2004-14, 16), an Open era record. Federer has, however, lost his last five semi-finals in Melbourne (2011-14, 16).
6 – Australian Open finals for Djokovic (2008, 2011-13, 2015-16), the Open era record. He is followed by Stefan Edberg, Federer and Murray – with five finals apiece.
Djokovic is 6-0 in Australian Open Finals (100%); only four players in the Open era have a 100% record in finals at a single Grand Slam (with at least six finals)
Björn Borg (6-0) – French Open
Pete Sampras (7-0) – Wimbledon
Rafael Nadal (9-0) – French Open
Novak Djokovic (6-0) – Australian Open
6 – Times Djokovic has won the Australian Open (2008, 2011-13, 2015-16), the Open era record. He is followed by Agassi and Federer with four Australian Open Titles apiece. The Serb shares the all-time record with Aussie great Roy Emerson who also won six titles down under (1961, 1963-67).
90.57% – Match winning percentage for Agassi at the Austrailain Open (48-5), the Open era record (for minimum 20 wins). Djokovic has a 90.48% match record (57-6) and is closing in.
14 – Consecutive match wins for Djokovic (2015-16). His last loss came at the hands of Stan Wawrinka (2014 quarter-finals).
80 – Match wins for Federer (80-13) the Open era record at the Australian Open. Federer has also played a record 93 matches at the Aus Open.
30 – Consecutive sets won by Federer from 2006-08. Agassi won 27 consecutive sets in 2003-04.
51 – Men have reached the Australian Open Final in the 48 editions in the Open era.
4 – Australian Open Finals between Djokovic and Murray; the record for most Open era finals meetings in Melbourne → 2011, 2013, 2015-16 (All won by Djokovic). The only other pair to have played in four finals at a single Grand Slam is Federer-Nadal (French Open).
2 – Australians have reached the final since the event has moved to the Melbourne Park (1988). Pat Cash (1988) & Lleyton Hewitt (2005) – both finished as runners-up.
9 – Appearances for Czech Petr Korda (1998) and Swiss Stan Wawrinka (2014) before winning the Aus Open, the Open era record for most appearances before winning the title. Murray will be attempting to win his 1st Australian Open on his 12th visit (could set a new record!).
12 – Successful title defences have occurred at the Aus Open. Djokovic leads the pack with three (2011-13, 2015-16).
26 – Players have won the Australian Open title in the Open era