The former world number one had hoped to build on the momentum that had carried him into the quarter-finals of the Citi Open before he pulled out of the Washington tournament citing fatigue.
But it was world number 17 Pouille who proved to be the more resourceful as he claimed his first win in five tries against Murray.
Murray, whose ranking plummeted into the 800s last month but has now risen to 375, has fallen at the first hurdle in two of the four tournaments he has contested this year.
"I only lost four more points in the match than him," said Murray, who won 82 points to Pouille's 86.
"It was tight. He's a top 20 player. If I can improve by 10, 15 percent, you turn a lot of those matches around."
Pouille said he was pleased with how he fought against the former world number one.
"I'm very happy, especially with the way I fought until the end," he said.
"I tried to do my best in the third set and then until the end I played very aggressive and I'm very pleased with that."
American Sam Querrey overcame 38 aces by ninth seed John Isner to send his friend and compatriot packing with a 6-4 6-7(5) 7-6(5) win.
The win was the first time Querrey has come out on top in a third set tiebreaker this year after losing seven in a row.
"I've lost a handful of tough matches this year but I feel like I’m starting to play better now, a little more consistent," the 30-year-old Californian said.
"Hopefully I can end the year on a strong note. Usually I feel like I play my better tennis at the beginning of the year so I'm going to try to flip it and play better at the end this year."
Spain's Pablo Carreno Busta, Britain's Kyle Edmund and Japan's Kei Nishikori also were first round winners.
The tournament lost its top seed when Spanish world number one Rafael Nadal withdrew after winning the Rogers Cup on Sunday.
World number two Roger Federer, who skipped the Toronto event, is now the highest seed.
(Reporting by Gene Cherry in Raleigh, North Carolina, and Rory Carroll in Los Angeles; editing by Pritha Sarkar / Ian Ransom)
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