The second seed lost to American qualifier Tommy Paul, who exhibited poise and consistency to win the match 6-4 6-4.
Zverev was hampered by double faults, hitting nine in total. The German lost his opening service game and Paul never looked back, taking the first set in 46 minutes. Although Zverev was able to maintain parity till 4-4 in the second set, a crucial double fault on break point was enough to hand the match to the American.
This victory is undoubtedly the biggest of Paul's career, and his first against a Top 10 player. The 22-year old has been experiencing a breakout season, reaching the semifinals in Adelaide and attaining a career-high of No.66 in the ATP rankings.
Paul next faces compatriot John Isner, who triumphed 6-3 7-6(4) over American qualifier Marcos Giron. The fifth seed hit 28 aces, bringing his total to 50 for the entire tournament. Isner defeated Paul 6-3 6-3 in their sole encounter at the Cincinnati Masters in 2017.
Britain's Kyle Edmund produced the second upset of the day, defeating fourth seed Felix Auger-Aliassime 6-4 6-4 in an hour and 43 minutes. The in-form Canadian was coming off two consecutive final appearances this month, finishing second in Rotterdam and Marseille. Perhaps fatigue finally caught up with the 19-year old, as he was unable to overcome the fast-paced method of play employed by his British opponent.
Conversely, Edmund extended his winning streak to seven matches after capturing the title in New York two weeks ago. The Brit will face American Taylor Fritz, who defeated France's Ugo Humbert 6-4 6-1 in 79 minutes.
Serbian Dusan Lajovic also joined the list of seeded casualties, falling to unseeded Soonwoo Kwon. The Delray beach quarterfinalist defeated the eighth seed 7-6(2) 6-0 to advance to his second consecutive quarterfinal.
Seventh seed Grigor Dimitrov saved two match points in the final set to avoid being upset by Frenchman Adrian Mannarino. The 2014 champion prevailed 6-7(8) 6-2 7-6(2) in a thrilling late night encounter that lasted almost 3 hours. He faces the winner between third seed Stan Wawrinka and Spaniard Pedro Martinez.
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