The visitors finished on 169-5 after their 20 overs with Nizakat Khan's 62 and 49 from Babar Hyatt the pick of their innings.
Ireland lost captain William Porterfield in the second over, putting the home side on the back foot.
Greg Thompson's 44 and Kevin O'Brien's 32 led Ireland's batting effort, but they ultimately fell well short.
Ireland closed on 129 all out, with Porterfield's men needing a much-improved display when the teams meet again on Tuesday.
The Irish defeated Hong Kong in the Intercontinental Cup match at Stormont last week.
There was better news for Ireland's Women, who beat Bangladesh by six runs in a rain-reduced, 10-over game.
Clare Shillington was Ireland's top scorer with 26, as she led the home side to 54-8, while Bangladesh could only reach 48-6.
Hong Kong beat Ireland by 40 runs in the first of the two-match Twenty20 series at Bready.