Surrey swing bowler Tom Curran, playing in only his third ODI, took 5-35 as the hosts were 247 all out to give England a 4-1 series win.
Jason Roy gave the tourists a fine start with 49 from 46 balls at the newly-opened Optus Stadium, with close to 54,000 in attendance at the venue's first event.
Perth native Marcus Stoinis scored 87 off 89 balls to set up the run chase, with Australia cruising at 189-4 in the 34th over.
The game would however turn in England's favour with a run of four wickets for just 14 runs.
Curran claimed two of those wickets and then bowled Adam Zampa and Tim Paine (34) to seal the win and claim his maiden ODI five-for.
Both England and Australia will now turn their attention to the Twenty20 tri-series that also involves New Zealand.