Rahmatullah Gurbaz’s fifty led the visitors to reach 189-5.
In their response, Ireland suffered right away after losing their first two players, Paul Stirling for a duck and Andrew Balbirnie for one, leaving them at 19-2.
Despite a late unbroken 58 from George Dockrell, they fell short with 167-9 as the wickets kept falling regularly.
Ireland had a slim advantage heading into the last two games on Monday and Wednesday after winning the first two at the Belfast site.
Ireland won the toss and decided to play, but they may have regretted that choice as Gurbaz and Hazratullah Zazai put up an opening partnership of 90 runs in 11.2 overs (53 off 35 balls and 39 of 40 respectively).
As the Afghans finished with five wickets left, Ibrahim Zadran (36) and Najibullah Zadran (42) built on the foundations set by the openers.
Najibullah’s 18-ball 42 had five sixes. With a 2-29, Josh Little was the best bowler for Ireland.
Lorcan Tucker scored 31 off 21 balls, including six and four fours, to become the first top-five Ireland batsman to reach double figures.
When Dockrell and debutant Fionn Hand (36) linked up, the Irish were in dire straights at 85-7 in the 13th over. They added 74 runs for the eighth wicket in six overs, with the former hitting two sixes and six fours.
In the end, the home team never seemed to have a chance of winning, and their opponents emerged as deserving winners.
With the ball, Naveen-ul-Haq excelled with scores of 3-38.