Nadal appeared on his way to the semifinals at Melbourne Park when he won a dramatic third-set tiebreak but once he became injured in the fourth set Tuesday, it was apparent his stay at the year's first major would come to an end.
A limping Nadal called it quits early in the fifth set -- his first grand slam retirement since the Australian Open in 2010 against Andy Murray -- and Cilic triumphed 3-6 6-3 6-7 (5-7) 6-2 2-0 ret.
If there was some comfort for Nadal's fans, his perennially troubled knees weren't the issue. Instead, it looked like his right thigh was the problem.
The Spaniard, 31, has indeed endured tough times in Melbourne, despite edging great rival Roger Federer in a classic five-set final in 2009.
He injured his hamstring in the 2011 quarterfinals against David Ferrer, hurt his back in the warmup of the 2014 final against Stan Wawrinka and has now suffered the leg issue against Cilic.
Cilic next meets Kyle Edmund, who is admirably carrying the torch for Britain in the absence of the injured Murray as he upset last year's semifinalist Grigor Dimitrov 6-4 3-6 6-3 6-4.
Edmund wasn't alone in springing a surprise Tuesday, with the surging Elise Mertens becoming the latest unexpected women's semifinalist in Melbourne when the Belgian crushed Elina Svitolina 6-4 6-0. The fourth seed said she was banged up, too, bothered by a hip injury.
Edmund, who moved to England from South Africa aged three and is now based in the Bahamas, is just the sixth British man to go this deep at a grand slam in the Open Era and the first other than Murray since Tim Henman at the 2004 US Open.
"I am loving it right now, just the way I'm playing," Edmund told reporters. "I'm 23 years old, my first grand slam semifinal. First time I played on one of the biggest courts in the world, to beat a quality of player like Grigor. Of course, all these things I'm aware of.
"They're great feelings. You don't obviously play in the semifinals of a grand slam every day, or a quarters like today."
Henman usually doesn't travel to grand slams nowadays as he prefers to be at home but he was in attendance at Rod Laver Arena to watch Edmund's heroics.
Given Murray's absence and the second-round defeat of one of the women's favorites, Johanna Konta, world No. 49 Edmund has largely been the focus of the traveling British press, who outnumber just about every other nation in sending written media to tennis tournaments.
When asked how he was dealing with all the attention, Edmund quipped: "I know what it feels like to be Andy Murray for the last eight years!"
But Edmund also knows it is a good position to be in because it means he is still in the tournament.
First top-10 win
Edmund began his Melbourne campaign by ousting US Open finalist Kevin Anderson and in defeating Dimitrov, collected his first top-10 win in 15 attempts. He faces more top-10 opposition in Cilic.
As for Dimitrov, an accumulation of lengthy matches cost the third seed Tuesday. He needed five sets to beat the unheralded Mackenzie McDonald in the second round and four to see off Andrey Rublev thereafter.
He subsequently defeated Australia's Nick Kyrgios in a draining, three-set night match Sunday.
"I would say all the matches out here, especially I think from day one I was not playing well," said Dimitrov, the 2017 year-end winner who beat Edmund just a few weeks ago in Brisbane. "It took me a lot of work to get back to playing a decent match once again.
"Against Nick, for sure, you played the crowd, you played him, you played your own expectations. There's a lot of components that come into the game.
"In the same time, I was at least happy I found the way. But all that behind the scenes, what you do in order for you to feel better on the court, takes a lot out of you. Doesn't matter how fit I am, I think also mentally I was just a little bit tired."
Mertens may be a relative unknown to casual tennis fans but her start to 2018 suggests her sojourn in Melbourne is no fluke: The world No. 36 became the first player to successfully defend her title in Hobart on the eve of the Australian Open.
The 22-year-old Belgian was due to play Australian Open qualifying in 2017 but because of her deep run in Hobart, had to miss out. So this is her first time in the main draw.
"Didn't really have a lot of expectations here," Mertens, who rallied from a 0-5 deficit against home favorite Daria Gavrilova in the second round, told reporters.
"I played a qualifier first round, so I was expected to win. Not always easy, but yeah, as it moved forward, first round, second round, I didn't really expect to be in the semis."
In recent years at the Australian Open, Sloane Stephens, Eugenie Bouchard, Madison Keys and Mirjana Lucic-Baroni all landed in the semis unexpectedly.
Mertens grew up close to Kim Clijsters' home town of Bree and idolized the four-time grand slam winner. She trains at Clijsters' academy and has been in touch with her during the fortnight.
"She has been here before," said Mertens. "She has the experience, so it's always nice to talk to her. And also, for the emotions, to see what she has to tell me or can, yeah, communicate."
Mertens' next challenger is second-seed Caroline Wozniacki, who overcame a blip in the second set to beat Carla Suarez Navarro 6-0 6-7 (3-7) 6-2 following Nadal's defeat.
Wozniacki moved a match closer to winning a first major after losing a pair of US Open finals, one to Clijsters.