Both sides had early opportunities as John Yeboah headed wide for the hosts while Mastantuono had an effort blocked at close range. Cher Ndour could only find the side netting from a tight angle and Alex Jiménez dinked just wide as chances continued to flow.
Against the run of play, however, it was Venezia who opened the scoring at the first half’s midway point.
Gianluca Busio burst through the centre before feeding Akor Adams, who unleashed a venomous first-time right-foot effort into the far corner for his first ever goal in the Italian top-flight.
The hosts barely had time to enjoy their lead as they were behind by the half-hour mark, with Real Madrid loanee Mastantuono scoring twice in as many minutes.
First, he cut inside from the right and drove a fizzing left-foot drive into the bottom left-hand corner before collecting a loose ball moments later and placing an effort into the opposite corner via the post despite the desperate efforts of Venezia goalkeeper Filip Stankovic.
Fiorentina should have doubled their lead shortly before HT too, but Alieu Njie - also in search of his first goal for the club - was denied by the legs of Stankovic when played through on goal.
After the break, Fiorentina soaked up a period of pressure and struck a decisive third goal on the counter-attack with less than 25 minutes to go.
Substitute Mateo Pellegrino scored in back-to-back matches as he ran onto Nicolc Fagioli’s clearance from inside his own half before racing clear and firing left-footed into the bottom corner.
Thorir Johann Helgason later tested David de Gea from range before Mastantuono completed his treble.
The Argentine ran onto a looped pass from Ndour and the ball rebounded back off the 19-year-old and into the net after his initial effort was saved by Stankovic.
That wasn’t the end of the scoring, however, as Antoine Hainaut thumped a right-foot volley past De Gea to reduce the deficit with three minutes to go.
Despite that late rally, the damage had already been done for Venezia, with Giovanni Stroppa’s side conceding at least two goals for a sixth successive match this campaign.
Fiorentina therefore comprehensively ended a five-game losing streak in Serie A away H2Hs, leaving Venezia at the bottom of the table in the process.
Flashscore Man of the Match: Franco Mastantuono (Fiorentina)