The Irish total of 125-6 was modest and their Afghans reached the target with eight balls and five wickets to spare.
Paul Stirling was Ireland's top scorer with 25 as several batsmen failed to build on decent starts in Abu Dhabi.
An opening stand of 54 from Najeeb Tarakai (31) and Mohammad Shahzad (29) then put Afghanistan in charge.
The innings wobbled a little as Jacob Mulder removed Shahzad and skipper Asghar Stanikzai as Afghanistan slid to 99-5 but the experienced Mohammed Nabi (26 not out) saw his team home without further alarm.
Earlier, Ireland were given a solid platform as Stirling shared an opening partnership of 36 with stand-in opener Stuart Poynter (18).
However once Nabi's off-spin broke the stand, Afghanistan's spinning triumvirate gained control of the innings as Ireland's inability in recent times to produce decent Twenty20 totals continued.
Amir Hamza and talented leg-spinner Rashid Khan also picked up a brace of wickets as the Irish stuttered to 125-6 with Gary Wilson (23) the only batsmen to join Stirling in passing 20.
In Saturday's other game, Scotland beat Hong Kong by 24 runs.
Ireland will have to beat Namibia in their next game in the round-robin tournament in Abu Dhabi on Tuesday to keep alive their hopes of reaching the semi-finals, before they face their UAE hosts in the final group game on Wednesday in Dubai.
The week-long competition aims to give more T20 tournament experience to the eight associate countries involved.
John Bracewell's Irish side suffered a blow on Friday when Andrew Balbirnie and Stuart Thompson were ruled out of the tournament by injury.
Batsman Balbirnie has a glute strain, while all-rounder Thompson suffered an ankle injury during training on Friday, which led to Poynter and Lorcan Tucker being called up as late replacements.
Ireland were handed a five-wicket defeat by Afghanistan in their opening game in the inaugural Desert T20 tournament in the United Arab Emirates.