The victory in just over two hours put the 33-year-old world number three into the third round of his final tune-up tournament for the US Open.
The Swiss great, who had notched his 200th Masters match win against Lleyton Hewitt at Cincinnati five years ago, arrived at the tournament he has won five times off a runner-up finish to Jo-Wilfried Tsonga in Toronto.
He delivered a dominant third set to finally subdue the 46th-ranked Pospisil, who was a finalist last month in Washington. He stretched his career record over the Canadian to 3-0.
"It's a nice round number," said Federer of his most recent achievement, "I've had some more important ones than the one today, but nevertheless it's nice to reach such milestones.
"I was one of those guys who struggled early on in the Masters 1000. I know how hard it is to win all these matches because it's always against top 50 players, if not top 20, if not top 10.
"From that standpoint, I'm obviously happy that it is at 300, it's nice.”
After taking the first set in the tiebreaker, Federer was broken in the 12th game of the second as the challenger forced a deciding set.
But Federer powered through the third, breaking his opponent twice on the way to victory and finishing with 23 winners and 21 unforced errors, with six aces along the way.
"The transition (from one event to the next) is always a tough one," said Federer, "We don't have enough days.
"You can't expect too much, we just hope to get through the first match in tough conditions."
While Federer safely followed top seed Novak Djkokovic into the third round, two of the men's top eight were toppled.
Taiwan's Lu Yen-Hsun stunned Czech fourth seed Tomas Berdych 3-6, 6-3, 6-4 while Poland's Jerzy Janowicz upset number seven Grigor Dimitrov 6-4, 3-6, 6-3 – four days after the Bulgarian played a semi-final in Toronto.
Sixth seed David Ferrer fought through three tiebreakers to beat German Philipp Kohlschreiber 6-7 (4/7), 7-6 (7/4), 7-6 (7/4), and eighth-seeded Andy Murray advanced with a smooth, 6-3, 6-3 victory over Portugal's Joao Sousa.
Murray, who lifted the Cincinnati trophy in 2008 and 2011, is searching for his first title since winning Wimbledon 13 months ago.
Since returning in January from back surgery, Murray has enjoyed only modest results, with his best 2014 showings semi-finals at Roland Garros and Acapulco.
Both of the Scot's Cincinnati titles came in finals against Djokovic, who has won every Masters 1000 title save this one.