The third seeds won 6-4 6-3 to clinch their first title at an ATP World Tour Masters 1000 tennis tournament.
Bhupathi and Knowles played a solid service game and didn't face a single break point in the match that lasted one hour 12 minutes.
The Indo-Bahamian duo had earned a place in the final by ousting defending champions Daniel Nestor and Nenad Zimonjic in the semi-finals.
Bhupathi, the Open Era doubles title leader at the Rogers Cup, collected his fifth Canadian title with a fourth different partner.
The 35-year-old had earlier lifted the doubles trophy in 1997 (with Leander Paes), 2003 (with Mirnyi), 2004 (with Paes) and 2007 (Pavel Vizner).
"I was joking with my coach that now I should probably buy a flat here since it is my fifth title in Canada!" Bhupathi said after the win.
The 37-year-old Knowles returned to the winner's circle in Canada for the first time since capturing his maiden ATP World Tour title on his tournament debut 16 years ago (with Jim Courier). He had finished runner-up in 1996 and 2002 with long-time partner Nestor.
"This is a very special tournament for me because this is where I won my first ATP title with Jim Courier...in 1993, just a couple of years ago," said Knowles.
"Mahesh has had so much success here in the past and has carried me to the title," he added.
Bhupathi and Knowles, who became a regular pair last season, improved to a 4-6 record in tour-level finals with their team's first title since last October in Basel.
They were finalists at the Australian Open and at the Barcelona Open Banco Sabadell earlier this year.
Bhupathi has now won at least one ATP World Tour title every year since 1997, with a total of 45 titles to his name.
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