AFP Sport looks at the 36-year-old Spanish great's earliest Grand Slam exits since winning his first major in 2005 at Roland Garros.
Wimbledon 2005: Second round
Nadal was playing his first major since winning the French Open as a 19-year-old. His game was still that of a clay-court specialist as he fell in four sets to big-serving Gilles Muller from Luxembourg. Muller would beat Nadal again on grass 12 years later in a five-set thriller in the round of 16.
Wimbledon 2012: Second round
Despite two triumphs at the All England Club, in 2008 and 2010, Nadal experienced more trouble on the Wimbledon grass. He went down in a five-set defeat to Lukas Rosol, who also employed a high degree of gamesmanship to unsettle the usually unflappable Spaniard.
Wimbledon 2013: First round
The following year marked Nadal's first-ever opening-round exit at a Slam when he was shocked in straight sets by diminutive Belgian Steve Darcis. It was an uncharacteristically lackadaisical performance from the Spaniard, with Darcis at the time becoming the lowest-ranked player to knock him out of a Slam.
Wimbledon 2015: Second round
Nadal's love-hate relationship with Wimbledon continued as he went out in the second round once more. This time it was to fiery German-born Dustin Brown, who knocked out the Spaniard in four sets with a combination of big hitting and deft touch.
Australian Open 2016: First round
The years 2015-2016 marked a nadir in the career of tennis's most decorated men's player with an opening-round exit at the Australian Open which raised questions about whether the end was near. A five-set loss to compatriot Fernando Verdasco also came in the middle of his longest spell without a Grand Slam triumph.
Australian Open 2023: Second round
Nadal has struggled since withdrawing from Wimbledon at the semi-final stage last year and came into 2023 low on confidence and looking less than fully fit. He edged a first-round win over cramping Briton Jack Draper before being outplayed 6-4, 6-4, 7-5 by McDonald on Rod Laver Arena, as a hip injury took its toll.