Opener Usman Khawaja was all set for his third hundred this month but fell for 98 to fast bowler Usman Shinwari.
Glenn Maxwell, meanwhile, celebrated his 100th one-day international with an impressive 33-ball 70, Shaun Marsh scored 68-ball 61 and captain Aaron Finch made 69-ball 53 to put Australia in control at halfway stage.
It was Maxwell's third consecutive 50-plus score, giving him a timely boost in intense competition for the middle-order spots for the World Cup starting on May 30 in England and Wales.
Khawaja and Finch laid the foundations with a solid 134-run opening stand but it was Maxwell's 10 fours and three sixes that helped Australia to 107 runs in the last 10 overs.
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Pakistan lost opener Abid Ali, who scored a century on debut in the last match, for a golden duck in the first over but Shan Masood and Haris Sohail got the run chase on track with a steady partnership of 108 for the second wicket.
Leg-spinner Adam Zampa celebrated his 27th birthday by trapping Masood (50) leg-before to give Australia a crucial breakthrough, before Maxwell's off-spin removed Mohammad Rizwan for 12.
Sohail smashed his second century of the series but holed out to paceman Kane Richardson for 130 when the run-rate pressure forced him to go for broke in the 41st over.
Captain Imad Wasim scored an unbeaten 50 to reduce the deficit but the task proved too big for Pakistan who finished 307-7 after 50 overs.
"It's very satisfying," said Australia coach Justin Langer.
"We came here in September and Pakistan showed us how to play cricket (with 3-0 Twenty20 series win). We worked really hard in the summer to turn it around, and 5-0 is a great result.
"Everyone in world cricket is working towards the World Cup, and it's always nice to go into the tournament with confidence. We've got some now."
The win was Australia's eighth in a row after their 3-2 comeback victory in the series in India this month.
(Reporting by Hardik Vyas in Bengaluru, editing by Pritha Sarkar)
