Centre court at the sprawling Lindner Family Tennis Center turned into a parade of champions as fans savoured an action-packed day that began under a bright morning sun with Wimbledon winner Murray breezing past Russian Mikhail Youzhny 6-2 6-3.
Australian Open champ Djokovic beat Argentine Juan Monaco 7-5 6-2 to move a step closer to becoming the first player to win all nine World Tour Masters titles, before French Open winner Nadal dispatched German Benjamin Becker in equally impressive fashion, 6-2 6-2, under the floodlights.
Nadal, who has been in superb form opening up his hardcourt campaign with a win in Montreal on Sunday, continued to build momentum towards the US Open later this month and extended his hardcourt winning streak to 11 matches.
"I played well tonight, I should be very happy the way that I played since the beginning," Nadal said. "Just for a few games the serve was down a little bit. For the rest, I think I played a great match.
"When you change cities, change a little bit of weather, the feelings on the ball is different and when you have these kind of tournaments back to back it's not easy, but I'm very happy with the way I played this afternoon and the way that I adapted the game."
Djokovic was all business on an unusually chilly afternoon on the outskirts of Cincinnati as he eased past Monaco.
"Between 4-1 and 4-5 (first set), four quite bad games for me," Djokovic said. "I stopped moving my legs. I didn't really go for my shots.
"I let him kind of dictate the play and wait for his mistake, which was not the right tactics.
"But all in all, I expected a little bit of a challenge for myself especially because he's a good player but also because it's the first match here in Cincinnati, which has different conditions from what we played in Montreal."
Twice before, in 2008 and 2011, world number one Djokovic and number two Murray have met in the Cincinnati final with the Scot winning on both occasions.
But this year the big Serb, who has four runner-up finishes on the Ohio hardcourts, will be determined to be the last man standing and become the first player to complete what the ATP Tour has dubbed the 'Career Golden Masters' and win all nine World Tour Masters titles.
Murray and Djokovic have been making a habit of meeting when something big is on the line.
They clashed in the finals of three of the last four Grand Slams with Djokovic coming out on top in Australia and Murray the winner at the US Open and Wimbledon.
In other matches, seventh seed Argentine Juan Martin Del Potro, the 2009 US Open champion, tamed Russian Nikolay Davydenko 7-5 7-5 while top ranked American John Isner beat Frenchman Richard Gasquet, the eighth seed, 7-6 (6) 6-2.
Canada's Milos Raonic, who moved into the top 10 for the first time this week, continued his good form disposing of Serbia's Janko Tipsarevic 6-4 7-6 (4).
Cincinnati Masters results
Tommy Robredo (Spain) beat 9-Stanislas Wawrinka (Switzerland) 7-5 3-6 6-3
4-Rafa Nadal (Spain) beat Benjamin Becker (Germany) 6-2 6-2
6-Tomas Berdych (Czech Republic) beat Jarkko Nieminen (Finland) 6-3 6-2
Dmitry Tursunov (Russia) beat James Blake (U.S.) 6-4 6-4
12-Milos Raonic (Canada) beat Janko Tipsarevic (Serbia) 6-4 7-6(4)
1-Novak Djokovic (Serbia) beat Juan Monaco (Argentina) 7-5 6-2
John Isner (U.S.) beat 8-Richard Gasquet (France) 7-6(6) 6-2
Feliciano Lopez (Spain) beat Jeremy Chardy (France) 6-4 2-2 (Chardy retired)
7-Juan Martin Del Potro (Argentina) beat Nikolay Davydenko (Russia) 7-5 7-5
David Goffin (Belgium) beat Vasek Pospisil (Canada) 7-5 1-6 7-6(6)
11-Tommy Haas (Germany) beat Marcel Granollers (Spain) 6-4 6-1
2-Andy Murray (Britain) beat Mikhail Youzhny (Russia) 6-2 6-3