The Portuguese guided in his side's third goal late on after Alvaro Morata and Federico Chiesa struck earlier in the second half to put Andrea Pirlo's side in a commanding position.
Ronaldo, who also hit the post with an effort in the first half, becomes the first player to score at least 20 goals in each of the last 12 seasons in Europe's top five leagues.
The gap still leaves Juventus with work to do in their quest for a 10th consecutive league title.
"If we don't win it at the end of the season we will congratulate the winners, but we must die on the pitch first, until we're told that there are no more points left to play for," Morata told Sky Italia.
"That's what we must do, as long as we have a mathematical chance, we will fight until the end."
Pirlo's side slipped up with a draw at mid-table Hellas Verona on Saturday and knew they could not afford any more mistakes after falling 10 points behind league leaders Inter.
But they lost defender Matthijs De Ligt to injury in the warm-up and struggled in the opening period, coming closest when Ronaldo dribbled into the box and curled a shot off the foot of the post.
The double introduction of Morata and Federico Bernardeschi with half an hour remaining proved decisive, as the winger teed up the Spanish striker to score his first league goal since December within 60 seconds of coming on.
"Morata is a fundamental player for us; he has a lot of quality, knows how to work with the team, how to attack the space and score goals," Pirlo said.
"He's the player that we wanted. Unfortunately he has been missing lately but now we hope he can get back to his best quickly."
Bernardeschi was involved again as he found Chiesa in the box for Juve's second goal, with the latter scoring on the rebound after his initial effort was parried by Ivan Provedel.
Ronaldo then broke upfield and scored with a composed finish in the 89th minute to seal the win, although Spezia squandered the chance for a consolation goal when Wojciech Szczesny saved Andrey Galabinov's penalty with the final kick of the game.