The Lions - captained for the first time by Nottinghamshire's Joe Clarke, in the absence of Lewis Gregory - batted first but on another turning track were bowled out for 169.
Clarke himself made an unbeaten 60, while Ollie Pope (46) helped him put on 59 for the fourth wicket. Zohaib Khan took four wickets for the hosts to initially dismiss Pope and then remove the Lions' middle order, putting the game firmly in his side's favour.
On a pitch where a total in the region of 230 may have been competitive, Pakistan A were left needing 170 to win and they did so comfortably, for the loss of just three wickets despite another good spell from Mark Wood - so far England's stand-out bowler on tour.
The two teams will reconvene for two T20s on December 7 and December 8.
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