A delirious 70,000-strong home crowd at the Principality Stadium watched Wales bring an emphatic end to their losing run, 1,099 days after their last Six Nations success against Italy three years ago.
Wales remained bottom of the standings, although they picked up a bonus point and there is a chance they might avoid the wooden spoon if England lose heavily to France in the last game of the tournament in Paris later on Saturday.
Aaron Wainwright scored Wales' opening two tries in the first half, and skipper Dewi Lake added another for a 21-0 half-time lead.
Dan Edwards, who kicked over four conversions, scored a fourth try soon after the break and added a drop goal to put Wales 31-0 up in the 48th minute.
Italy, coming into the match on the back of a first-ever victory over England, got their first points with a mauling try from substitute hooker Tommaso di Bartolomeo in the 53rd minute and scored a second through Tommaso Allan as they attempted a late recovery.
The third try was the final action of the match with Paolo Garbisi scoring but came far too late to spoil the home party.
Wales opened the scoring after 14 minutes when they won a line out and Wainwright burst through several tackles to carry the ball over.
He finished off a line-out drive for the second 11 minutes later and Lake also scored from a line-out maul.
The Wales forwards drove to within 10 metres of the Italian line to set up their fourth try three minutes into the second half and Edwards raced over.
Italy's first try came when they kicked a penalty to the corner and rumbled over with Di Bartolomeo emerging as the scorer. Allan's try was followed by two efforts that fell narrowly short before Garbisi went over from Lorenzo Cannone's offload.
The win will be a major boost for the beleaguered Welsh, who have made dramatic strides after conceding 102 points in opening losses to England and France.
Scotland were five minutes from losing in Cardiff before winning 26-23, and Wales lost 27-17 to Ireland in Dublin last weekend but were within one score until four minutes from time.
Wales had previously suffered 25 losses in 27 internationals since the 2023 World Cup, with the only two victories in that time coming against Japan.
