The 10th-seeded American had 13 aces in a 6-4, 6-7 (4), 6-3 loss to Dodig in the Croatian's first singles match in more than two months because of a broken rib. Isner managed to win a second-set tiebreak to stay alive, but Dodig earned a big break in the third set to grab control again.
Isner lost 6-7 (5), 6-3, 7-6 (6) to countryman Steve Johnson at the Citi Open in Washington on Wednesday, and then complained about his secondary court assignment. The loss to Dodig came on a grandstand court at Rexall Centre.
The match was originally scheduled for the afternoon in the stadium, but rain wreaked havoc on the day's schedule.
''Obviously it was not easy,'' Dodig said. ''It was long day for us, and of course changing the court it's also a little bit like making you to think about it.''
Isner was not made available to reporters.
In other night action, 13th-seeded Jo-Wilfried Tsonga beat fellow Frenchman Edouard Roger-Vasselin 7-6 (3), 6-1, American qualifier Michael Russell eliminated France's Nicholas Mahut 6-3, 6-3 and Feliciano Lopez beat fellow Spainard Roberto Bautista Agut 7-6 (7), 3-6.
The nightcap on center court featured Canadian wild card Peter Polansky beating 2013 Wimbledon semifinalist Jerzy Janowicz, 7-6 (5), 6-4.
Benneteau advanced with a 6-1, 6-2 victory. The 32-year-old Frenchman to adjust on the fly after the second rain delay, which lasted two hours.
''I tried to keep the same momentum and the same rhythm of the match,'' Benneteau said. ''I just tried to stay focused to be able to play the same way.''
Benneteau was leading 4-1 in the first set when the first brief rain delay occurred. He was up 4-2 in the second when storms moving through the Toronto area halted action across the tournament.
''The rain delay, it's never easy but it's for both players,'' he said. ''I had two break points before, 15-40 and then a deuce. So it's never easy.''
Benneteau also said it's never easy facing Hewitt, even though the Aussie is 42nd now and 11 years removed from being atop the world rankings.
''He's a great fighter and to beat him you have to play solid,'' Benneteau said. ''You have to do a good match. It's the kind of player that if your level is not good enough, you don't win.''
No. 15 seed Marin Cilic also moved on with a 6-2, 4-6, 7-5 win against Denis Istomin. The Croatian said Istomin was dealing with a shoulder injury that led to some unpredictability.
''He had some shots were coming off good, some not, and it was difficult to know what was going to come,'' Cilic said. ''It got a bit complicated.''
In other early action, France's Jeremy Chardy beat Argentina's Federico Delbonis, 6-3, 5-7, 6-4, French qualifier Benoit Paire defeated Colombian Alejandro Falla, 6-7, 6-4, 6-2, and American qualifier Tim Smyczek downed German qualifier Tobias Kamke, 6-3, 6-2.
The lengthy rain delay caused some changes to Monday's schedule. The Rogers Cup Hall of Fame induction ceremony was also postponed because of the weather. Stefan Edberg and former Rogers Cup Master of Ceremonies Don Goodwin will now be inducted Tuesday night.