Federico Bernardeschi and Khouma Boubacar scored before the break in Lisbon and a Tonel own goal made it three before Giuseppe Rossi scored his first goal since May last year after injury to clinch the win.
Fiorentina are second in their group, three points behind Basel, who beat Lech Poznan 2-0 in Switzerland.
Fiorentina were not the only Italian winners, with Lazio coming from behind to beat nine-man Saint-Etienne 3-2 in Group G and Napoli winning 2-0 at Legia Warsaw in Group D.