Matthew Wade and captain Michael Clarke made 75 apiece as Australia posted a total of 272 for eight in 50 overs.
Despite a stand of 86 between Asghar Stanikzai and Mohammad Nabi, Afghanistan fell well short on 206 as Mitchell Starc took four for 47.
Clarke won the toss in the one-off one-day international in Sharjah and elected to have first use of a wicket he described as "concrete", perfect for batting.
David Warner hit four boundaries as he contributed 24 to an opening stand of 37 with Wade and when he edged Shapoor Zadran to wicketkeeper Mohammad Shahzad, Clarke joined Wade at the crease for a second-wicket stand of 131.
Nabi, who finished with two for 50, ended wicketkeeper Wade's 108-ball innings with a sharp return catch and removed debutant Glenn Maxwell for two in his next over. Clarke was stumped off Samiullah Shenwari after facing 94 balls and hitting three fours and two sixes, but Michael Hussey (49) and George Bailey (23) provided some late impetus.
Karim Sadiq took two for 22 in six overs and Zadran two for 60 in eight.
Afghanistan lost opener Javed Ahmadi for a duck and Sadiq made 17 with three fours before, like Ahmadi, he was bowled by Starc. Shahzad made 11 and captain Nawroz Mangal failed to score, but from 49 for four Stanikzai and the initially slow-scoring Nabi enjoyed a fruitful partnership.
Remarkably, Nabi's six from his 26th ball trebled his score, but he then cut loose, making 46 from 60 with four sixes and three fours. Any serious thoughts of chasing the target had been put to one side as the minnows simply enjoyed the experience, and Stanikzai advanced to a measured half-century from 95 balls with only three boundaries.
He then hit three more in one Starc over before dragging the last ball straight to Clarke at mid-wicket and though Gulbodin Naib hit three sixes in his 22 from 17 balls, Australia wrapped up a 66-run win.