One day after they thrashed Barcelona 4-0, a much-changed Reds team went down by the same scoreline in Germany.
Jurgen Klopp's former club took the lead from the penalty spot in the 15th minute after Andre Wisdom was adjudged to have handballed in the area, allowing Daniel Brosinski to place the ball beyond Alex Manninger from 12 yards.
There was an element of controversy about the penalty decision, but Liverpool had only themselves to blame for Mainz's second, Jhon Cordoba capitalising on lacklustre defending from the Reds to fire past Manninger at the near post on the stroke of half time.
Mainz added a third on the hour mark after Yunus Malli gained possession in midfield, powered forward and blasted the ball past the Austrian shot-stopper to add some extra gloss to the scoreline.
It became a rout in the 75th minute when Japan international Yoshinori Muto got his head to a cross six yards from goal and beat Manninger for the fourth time.
Liverpool thought they had pulled one back with nine minutes remaining when Danny Ings poked home from close range, but the goal was contentiously ruled out for offside.