The dominant hosts scored only one try in the first half, through Bundee Aki.
Andrew Conway's quickfire double and a magnificent Garry Ringrose effort after the break saw Ireland accelerate away from the injury-ravaged visitors.
Only Taine Basham's late try saved Wales the ignominy of a scoreless defeat.
Wayne Pivac's side remain without a victory in Dublin since 2015 and have rarely looked less likely to win in the Irish capital as they were stifled throughout by an impressive Irish defence.
Given the extent of their injury list it was always going to be a tough opening assignment for the defending champions, yet the manner of their performance will provide great cause for concern as they begin preparations for Scotland in Cardiff next week.