The 30-year-old Spaniard has never won in Miami despite being a four-time finalist and he expects plenty of work to get past Fognini and make it a fifth appearance.
"We know each other very well. He has beaten me a couple of times and so it will be a good test. I will need to play my best," said Nadal.
Fognini has three wins from 10 meetings with the Spaniard, the most recent coming on clay in Rio de Janeiro in 2015.
The 29-year-old world number 40 showed plenty of confidence as he took the game to his Japanese opponent from the outset.
It was the Italian's first victory in three tries over Nishikori and his first Masters series quarterfinal win since 2013, when he reached the last four in Monte Carlo.
Nishikori earlier said he had not felt in top shape for the contest.
"I wasn't 100%, physically, I mean, it was tough conditions for me," he said, referring to the heat on the mid-afternoon centre court.
"But it was the same for him. He was playing a lot of long matches, but I think he still played good enough to beat me," he added.
Fognini, cheered on by his friend, former Italy footballer Christian Vieri, said he had come through a demanding test.
"It wasn't easy and I was just focused on my game. I am very happy, I'm in the semifinal, I'm playing well and I feel good again on the court," he said.
Roger Federer, Tomas Berdych, Alexander Zverev and Nick Kyrgios were involved in the remaining quarterfinals.
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