Lazio had taken the lead this evening with Stefan de Vrij, but after losing two defenders to injury and moving Lucas Leiva to centre-back, the Biancoleste fell apart.
Kalidou Koulibaly and José Callejón then scored early in the second half to overturn the deficit before Mertens put the icing on the cake with a superb goal.
Mertens had sprung the offside trap and Lazio goalkeeper Thomas Strakosha managed to get a hand to it, sending the Belgian wide.
Unfortunately for Strakosha, though, he could only parry away from the edge of his area, with the ball falling straight back to the Napoli striker.
Mertens still had a lot to do from 25 yards out, but the 30-year-old managed to steer a lob into the far top corner from a seemingly improbable angle.
Napoli rounded out the scoreline in stoppage time as Marco Parolo bundled into the back of Piotr Zieliński inside the area and Jorginho converted the resulting penalty.
Mertens, who scored 28 goals in Serie A last season, told Mediaset Premium afterwards what he was thinking as he scored the goal.
I saw the ball there and I thought of the shot. I turned around, saw the goalkeeper was getting slowly back to his line and there was a little gap, so I said to myself: go for it!
Honestly, it's thanks to my teammates if I am able to score goals like this. I am not Leo Messi, I'm not Maradona, I'm just Dries and I'm happy with that.