Wales led after the opening half thanks to tries by Kate Williams and Gwenllian Pyrs either side of Sofia Stefan's effort.
But the Italians turned the screw in the second-half as Francesca Granzotto, Silvia Turani, Vittoria Minuzzi and Aura Muzzo all crossed for tries, with Michela Sillari kicking 14 points.
It was a first home win for Italy in two years and a record victory over Wales, who lost all five games for the first time in their history.
The Welsh women's wooden spoon added to the men's side also finishing bottom in their tournament completes a miserable 2025 Six Nations for Wales.
Italy finished fourth in the table, behind third-placed Ireland but above Scotland in fifth.
England survived a sparkling French comeback to win the women's Six Nations rugby union decider 43-42 at Twickenham on Saturday.