He had been handed a first-round bye in Rome and, after all of Wednesday's play was postponed due to heavy rain in the Italian capital, Federer had to play twice on Thursday.
And for me, after the Australian Open they said that I was going to be No. 1. Rome has always been one of my favourite cities to visit, and I hope to be back next year.
The Swiss 20-time Grand Slam victor was playing in Rome to prepare for his return to the French Open for the first time since 2015.
It is not known if the injuries to both players will prevent them from competing in the French Open, which starts May 27.
Tsitsipas advanced after Federer - returning to clay after a two-year absence - retired with a right leg injury before their game.
Nadal has fallen in the semifinals of his last three tournaments, all on his favoured clay. And next up is Stefanos Tsitsipas, whom Nadal lost to in Madrid last week. I don't know what is going to happen at the French Open, tennis is very open now, even at the top. "So I was like, 'Maybe I slept on it and maybe it will go away.' But it didn't".
Halep bowed out in the second round of Rome in a three-set thriller against 19-year-old Czech talent Marketa Vondrousova, 2-6, 7-5, 6-3 on Thursday, allowing Osaka to secure the No.1 ranking after Rome and sit as the provisional No.1 seed at Roland Garros. She was yet to see a doctor but when she held her hand up for reporters to see it was clearly swollen.
"I woke up this morning and couldn't really move my thumb", Osaka said. "I tried to practise and grip my racket but I couldn't, and I kept feeling this pain when I tried to move my hand in different directions".
"I like the fact that I didn't play yesterday because I felt like I needed an extra maybe day of rest and recovery a little bit", said the Serb. "That's why I'm kind of confused right now because I literally woke up in the morning and couldn't move my thumb", Osaka said.
The Japanese star was due to meet Madrid Open champion and sixth seed Kiki Bertens for a place in the final four in Rome.
Schwartzman, 26, won 6-4, 6-2 in 87 minutes in the quarter-final for his first win in four meetings with former US Open finalist Nishikori.
The world number 24, a French Open quarter-finalist a year ago, has not dropped a set so far on the red clay of the Foro Italico and next faces either the top-ranked Djokovic or compatriot Juan Martin del Potro.