The Australian has endured another rollercoaster campaign but showed his class in Ohio, defeating the soon to be anointed world number one 6-2 7-5.
He will now meet David Ferrer in the semi-finals, following the veteran's 6-3 6-3 win over Dominic Thiem, and it will be interesting to see how he reacts to the occasion.
Kyrgios admitted after his win on Friday that facing the likes of Nadal on Centre Court at a tour event is exactly what he needs to bring the best out of him.
"Little kid playing on centre court of Cincinnati against Nadal, that's the way, the best has to come out," Kyrgios said.
"The problem for me is trying to bring it on an everyday basis, say, centre court of Lyon with, like, five people against Nicolas Kicker earlier this year, I lost.
"Tonight I'm playing Rafa and I win. These matches aren't the problem. It's those matches for me. It's easy to get up for these matches."
In the other half of the draw, John Isner defeated qualifier Jared Donaldson 7-6 7-5 and will now meet Grigor Dimitrov following his comfortable 6-2 6-1 triumph over Japan's Yuichi Sugita.