After a nail-biting 16-run win for the tourists in the opening match of the series of Monday, Ireland faltered with the bat as they were bowled out for just 79 in response to Afghanistan's 160 for eight.
Hazratullah Zazai top scored with 82 from just 54 balls and was ably supported by captain Asghar Afghan's 37.
Ireland's reply never recovered from a terrible start as Paul Stirling, Stuart Thompson and Andy Balbirnie were all dismissed by the third over with just nine runs on the board.
William Porterfield (46) and Gary Wilson (22) led a short-lived recovery but both fell to Rashid Khan, who finished with figures of 4-17, and no other Irish batsman reached double figures.
The hosts will aim to salvage some pride from the final match of the series on Friday before a three-match ODI series in Belfast next week.