Former Western & Southern Open champion Marin Cilic crashed out in the opening round, while Andy Murray played his first match of the year.
Cilic – the 2016 winner – was upstaged by Canada's Denis Shapovalov at the ATP Masters tournament on Saturday.
Another former champion, Murray, was also in action and he made it through to the second round.
The likes of Milos Raonic and Kevin Anderson also advanced behind closed doors in New York, with the event usually held in Cincinnati.
CILIC FALLS AT FIRST HURDLE
Cilic's preparations for the upcoming US Open in New York were dealt a blow following his 6-3 6-3 defeat to 12th seed Shapovalov.
With the ATP Tour back underway amid the coronavirus pandemic, Shapovalov got the better of Croatian star Cilic in 79 minutes.
Shapovalov's last win prior to COVID-19 halting the season was against Cilic at the Open 13 Provence in Marseille, and he trumped the 2014 US Open champion again thanks to a dominant serving performance.
Next up for Shapovalov is Jan-Lennard Struff, who was a 6-2 6-4 winner against Alex de Minaur.
MURRAY CELEBRATES WINNING RETURN
Former world number one Murray made his first appearance of 2020 and outlasted Frances Tiafoe 7-6 (8-6) 3-6 6-1.
Murray had not featured on the ATP Tour since claiming the European Open in Antwerp last October, however, the three-time grand slam champion made his return on Saturday.
The two-time Cincinnati champion saved a set point in the first set tie-break as he earned a meeting with fifth seed Alexander Zverev.
RAONIC AND ANDERSON WIN THROUGH
Former world number three Raonic hit 19 aces in a 6-4 6-4 victory over Sam Querrey, winning 87 per cent of his first-serve points.
Raonic will face either 10th seed Andrey Rublev or Daniel Evans in the next round.
A 7-6 (7-3) 4-6 6-3 win against Kyle Edmund saw Wimbledon and US Open finalist Anderson secure a showdown against fourth seed Stefanos Tsitsipas.
Meanwhile, 15th seed Felix Auger-Aliassime beat Nikoloz Basilashvili 6-4 6-1.
BERANKIS TO MEET DJOKOVIC
Qualifier Ricardas Berankis rallied past Tommy Paul 6-7 (4-7) 6-4 7-5 to set up a second-round clash with 17-time grand slam champion Novak Djokovic.
Handed a first-round bye, top seed and 2018 winner Djokovic is eyeing his second Cincinnati title following five runner-up appearances.
Second seed Dominic Thiem will open his campaign against Filip Krajinovic after the latter accounted for Salvatore Caruso 7-5 6-4, while 2019 finalist David Goffin plays Borna Coric, who benefited from a retirement against Benoit Paire.