With the series part of the World Cup Super League, defeat was a big blow to Ireland’s hopes of making the 2023 tournament.
Rashid Khan starred with bat and ball – his 48 helped Afghanistan post a total of 266-9 before taking 4-28 as the Irish fell short of the target.
That was despite Paul Stirling making it back-to-back centuries with 118.
Another 10 World Cup Super League points for Afghanistan moved them further clear of Ireland in the race to book an automatic spot in India.
Afghanistan won the opener by 16 runs and added a comfortable seven-wicket victory in the second ODI.
Ireland won the toss and decided to field, a decision that looked good as Afghanistan struggled to 167-7 at the Sheikh Zayed Stadium.
But almost another 100 runs were added, with Rashid’s 48 coming off 58 balls to frustrate the Irish attack.
Spinner Simi Singh took 3-37 and paceman Craig Young 3-61 before the Irish started their run chase, with Stirling the central figure.
The left-hand opener’s 128 on Sunday saw him overtake William Porterfield as Ireland’s all-time leading run-scorer across all formats.
He continued his superb form with 118 from 119 balls, his fourth century in his past six ODIs.
Ireland were well placed at 132-2 but Stirling failed to get the support required and it was a uphill task when he was dismissed to leave it 187-5 with almost 14 overs remaining.
Singh’s 20 and a 16 from Andy McBrine gave the Irish hope as they moved to 230-7 but the final three wickets fell without a further run being added.