Ireland won the toss and elected to bat but were bowled out for 198, a target that never looked enough against the Australians, who posted 199 for one for the loss of opener David Warner (48), with almost 20 overs to spare.
Smith (59) and Khawaja (82) were unbeaten in a second-wicket stand worth 126 from 129 balls.
Australia handed a debut to seamer Daniel Worrall, 25, and he posted figures of 1-43 in his 10 overs. Leg-break bowler Adam Zampa was the pick of the Australian attack with figures of 3-37.
Australia begin a five-match ODI series against hosts South Africa on Friday in Centurion.