The seven-time Grand Slam champion and reigning Wimbledon titlist is seeking his fourth Aussie championship in five years, having captured three straight of his four Melbourne crowns from 2011-13.
Up next for the great Djokovic, who has yet to drop a set through four matches here, will be eighth-seeded big-serving Canadian Milos Raonic, who is 0-4 lifetime against the Serb.
Meanwhile, the fourth-seeded Swiss slugger Wawrinka pulled out a 7-6 (7-2), 6-4, 4-6, 7-6 (10-8) victory over Spaniard Guillermo Garcia-Lopez.
Garcia-Lopez won the first five points of the fourth-set tiebreak and had five chances to force a fifth set at Melbourne Park, but Wawrinka saved all five before moving on.
Garcia-Lopez stunned Wawrinka in the first round at last year's French Open.
Wawrinka's quarterfinal opponent on Wednesday will be the fifth-seeded U.S. Open runner-up Nishikori, who handled ninth-seeded former French Open finalist David Ferrer of Spain 6-3, 6-3, 6-3 on Day 8 of the fortnight.
Looking ahead to his clash with Wawrinka, Nishikori said, "It's going to be a really tough match because I have seen him play on TV a couple of matches. Even today he was playing really good. He can hit balls forehand, backhand -- great backhand actually. He can hit from anywhere at the back. It's going to be a tough match. But obviously I'm in the quarterfinals, so no easy matches coming up. Hopefully I can play another good match.
"For sure it gives me confidence that I beat him in the U.S. Open. It's not like I can't beat him. It's going to be a fun match for sure."
Nishikori made history as he became the first Asian man to contest a Grand Slam final last year when he defeated three Top-10 players, including Wawrinka in five sets in the quarters, to reach the U.S. Open final.
The aforementioned Raonic had to outlast 12th-seeded Spanish lefty Feliciano Lopez, 6-4, 4-6, 6-3, 6-7 (7-9), 6-3, to reach the round of eight.
Raonic became the first Canadian man in the Open Era to reach the Aussie Open quarters and is also the second Canadian man in history to reach three major quarterfinals, following in the footsteps of Robert Powell at Wimbledon in 1908, '10 and '12.
"It's great to be doing what I'm doing and that it is making a difference," said Raonic. "It is, I guess, part of some history, if you look really deep. But at the end of the day, at the same time, I'm always pushing myself for what I want to achieve. I'm always sort of looking in the mirror and saying, 'That's who I have to compare myself to: to myself.'"
The quarterfinals will commence Tuesday, as third-seeded former world No. 1 Rafael Nadal will take on seventh-seeded Tomas Berdych and sixth-seeded Andy Murray will battle heavy Aussie crowd favorite Nick Kyrgios. Nadal beat Berdych in the 2010 Wimbledon final and is 18-3 lifetime against the big Czech.
The reigning French Open king Nadal is a 14-time Grand Slam champ, including an Aussie title in 2009. He's also a two-time runner-up in Melbourne, including last year when he was stunned by Wawrinka in the final.
Murray is a two-time major titlist who's lost in three Aussie Open finals.