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 Djokovic into the third round, three of the men's top nine 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 semifinal in Toronto. American Steve Johnson stopped ninth seed Ernests Gulbis 6-4, 6-4.
Number five Milos Raonic was untroubled by wild card Robby Ginepri 6-2, 6-2.
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 semifinals 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.
Murray improved to 3-0 over the 37th-ranked Souza, never trailing in the match that lasted 71 minutes.
He handed Souza his 21st loss of the season in either the first or second round, advancing on his first match point when Souza sent a service return long.
Murray broke Souza three times, and fired 16 winners matched by 16 unforced errors.
"I got the win and that's the most important thing," Murray said. "Conditions are completely different here to Toronto. But I hit the ball well from the back of the court today. I was able to control the ball well."
Number 11 American John Isner beat Australian Marinko Matosevic 6-3, 7-6 (7/1), Fabio Fognini, seeded 15th, dispatched Lleyton Hewitt 6-1, 6-4 while number 16 Spaniard Tommy Robredo beat Sam Querrey 6-2, 6-4.
Women's top seed Serena Williams advanced on cue, downing Australian Samantha Stosur 7-6 (9/7), 7-6 (9/7), but third-seeded Wimbledon champion Petra Kvitova stumbled out of the gate.
Ukrainian teenager Elina Svitolina toppled the Czech 6-2, 7-6 (7/2). The defeat comes on the heels of Kvitova's third-round exit at Montreal in another blow to her build-up to the US Open -- the last Grand Slam of the year that starts on August 25 at Flushing Meadows.
Wimbledon finalist Eugenie Bouchard was another casualty, falling to Svetlana Kuznetsova in three sets.