Romania, confirmed this week in the 2023 Rugby World Cup, started strong and led 6-5 on Friday.
But Italy asserted themselves just before halftime with two tries in two minutes to zip ahead 19-6.
Four more tries, and a second for centre Tommaso Menoncello, gave Italy their first win since 1991 in Romania and only their third victory away there.
Oaks flanker Vlad Neculau was sent off late for a high tackle on Renato Giammarioli, but they finished with a consolation try to replacement prop Alexandru Savin.
Italy retained only three players after struggling past Portugal 38-31 in Lisbon last weekend, but won a third straight Test. The Italians finish their summer tour against Georgia in Batumi next weekend.
Menoncello scored Italy's first try but Florin Vlaicu, playing his 129th Test and first since March 2021, kicked two penalties to put the hosts in front.
Italy squandered two attacking lineouts and missed a penalty from Tommaso Allan, making his first start since February 2020, but the flyhalf scored a try working off No.8 Toa Halafihi and debut scrumhalf Alessandro Garbisi.
A minute later, prop Ivan Nemer broke with support from hooker Gianmarco Lucchesi and lock Niccolo Cannone went over.
After the interval, a break by wing Pierre Bruno was finished by Garbisi, the younger brother of regular flyhalf Paolo, who joined him in the 58th minute.
An Ange Capuozzo counterattack led to Menoncello's second try, while Allan set up a try for midfielder Marco Zanon before replacement hooker Giacomo Nicotera went over.
Allan finished with 15 points and Italy recorded their second biggest margin against Romania.
Romania head to Uruguay for two Tests in Montevideo.
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