James Lawrence scored an own-goal to give Croatia an early boost after diverting a cross from Ivan Perisic in the 17th minute in Osijek.
Croatia looked to be the better side anyway as it moved on from recent inconsistent results.
Perisic doubled the advantage early in the second half for Croatia to rebound from a 2-1 loss to Hungary in Budapest. Substitute David Brooks cut the deficit for Wales with a deflected shot in the 77th.
With its second win in qualifying, Croatia took sole lead of Group E with six points, with Wales, Slovakia and Hungary trailing by three points but with a game in hand.
Source: FOX Sport