Top-10 seeds Marin Cilic, Tomas Berdych and Gilles Simon all fell to surprising losses at the Rogers Cup on Wednesday.
Reigning US Open champion Marin Cilic lost consecutive matches on the US swing, after Bernard Tomic earned a two-set win at the Rogers Cup on Wednesday.
Cilic's win over Kei Nishikori in the Flushing Meadows decider in September was reversed at the Citi Open last week when the Japanese won their semi-final - and Tomic continued Cilic's losing form with a 6-3 6-4 result in Montreal.
Conversely, Tomic has won six of his past seven matches - after defending his Bogota title in July - and has a clash with defending Rogers Cup champ Jo-Wilfried Tsonga for a spot in the quarter-finals.
Tsonga narrowly avoided a premature exit, the 10th seed edging past Roberto Bautista Agut 5-7 7-6 (8-6) 7-5.
The Frenchman, now at number 24 in the world, served for the first set, but was broken twice in succession as Bautista Agut took a shock lead.
Tsonga broke early in the second set, but the Spaniard returned the favour - leaving the Frenchman to serve to stay in the match twice late in the set.
The one-time Australian Open finalist won a tight tie-break - there was never more than one point between the pair - and Bautista Agut blinked in the 12th game of the third set, broken to 15 when he netted a tired forehand.
'Big four' representatives Rafael Nadal and Andy Murray both progressed in two sets, the latter completing his held-over contest with Tommy Robredo.
Second seed Murray was serving at 4-4 in the first set on Tuesday when rain halted his charge, but her returned to post a 6-4 7-5 win over the Spaniard.
Robredo's countryman Nadal - the seventh seed - was too good for Sergiy Stakhovsky 7-6 (7-4) 6-3 in what was the 14-time major champion's sixth straight match win since his shock second-round loss at Wimbledon in July.
Swiss third seed Stan Wawrinka exited in controversial fashion, retiring when trailing Nick Kyrgios 6-7 (8-10) 6-3 4-0.
Kyrgios had earlier delivered a stunning "banged your girlfriend" sledge to the Swiss two-time grand slam champion.
Fifth seed Tomas Berdych lost his first match since SW19 - going down to American qualifier Donald Young 7-6 (7-5) 6-3.
Other seeds joining Berdych and Cilic at the exit door were Gilles Simon (9), Grigor Dimitrov (14) and Gael Monfils (15).
Dimitrov blew one match point before going down to American Jack Sock 5-7 7-6 (7-5) 7-5, while Simon fell to a rejuvenated Mikhail Youzhny 6-1 6-4 - the Russian forced to qualify with his ranking slipping to 107th.
Sock will next face top seed Novak Djokovic, while Youzhny's next assignment is Nadal.
Gilles Muller blew six break-point chances in the third set - all of which came in the fourth game - but he held on to deny Monfils 6-3 3-6 7-6 (7-4).
Muller, of Luxembourg, has a date with Murray in the last 16.
Citi Open champion Nishikori, the fourth seed, extended his winning streak to seven matches with a 6-3 6-3 triumph over Pablo Andujar.
David Goffin ended the run of local favourite Sam Querrey 6-4 6-4, the 13th seed earning a third-round date with Nishikori.
Qualifier Ernests Gulbis continued his run, the qualifier surpassing Lukas Rosol 6-2 5-7 6-3.
As Gulbis did in his first-round match against Dominic Thiem and Sock did to Dimitrov, Jeremy Chardy saved two match points on his way past Leonardo Mayer 4-6 7-6 (7-4) 6-2.
John Isner, the 16th seed, ended the run of the last remaining Canadian in the singles draw, Vasek Pospisil, with a hard-fought 7-6 (7-1) 4-6 6-3 win.