The attacking midfielder scored a hat-trick against Genoa before the international break, and took his scoring run to six goals in three games with a superb brace against the Crociati.
The visitors set up to sit deep and spring counter-attacks, but two goals in four minutes from the ruthless Romans soon forced Fabio Liverani to tear up his game plan.
Mayoral latched onto a clever Spinazzola before sending a neat finish into the corner from a tight angle for his first Serie A goal.
Moments later, Mkhitaryan unleashed a thunderbolt of a half-volley from 30 yards out into the top corner to double Roma’s advantage, and the Armenian then tapped in a Rik Karsdorp cross at the back post before the interval.
It was Roma’s third consecutive league victory and moved Paulo Fonseca’s side up to third place in the standings.