Luciano Spalletti's side sit three points clear of second-placed Liverpool at the top of Group A, putting them in a commanding position to claim first ahead of their trip to Anfield on November 1, having run out 4-1 winners in the reverse game between the two sides last month.
Liverpool beat Ajax 3-0 in Amsterdam in the section's other match to take the race for first to the final matchday, and Rangers are still in with a chance of finishing third to claim a Europa League spot despite losing all five of their games in this season's competition.
Napoli opened the scoring in the 11th minute of the contest, with Giovanni Di Lorenzo's brilliant low cross being collected by Giovanni Simeone and then fired past the away side's goalkeeper Allan McGregor.
Rangers were two goals behind four minutes later, as Simeone grabbed his second in quick succession, with the forward heading a cross from Mario Rui into the back of the net.
Tanguy Ndombele rattled the crossbar in the 22nd minute, with the home side dominating the contest, and it only appeared a matter of time before the Serie A leaders would find a third goal.
Napoli's best chance of a third in the first period arrived in the 39th minute when Matteo Politano found Giacomo Raspadori with a clever cross, but the forward's header was straight at McGregor.
Alfredo Morelos then tested Alex Meret down the other end with a low drive, and the Colombian's effort proved to be the final major piece of action in the opening half of action.
McGregor prevented Simeone from completing his hat trick early in the second half by making a smart save with his leg, before Morelos saw a powerful volley blocked down the other end by Rui.
Napoli's third finally arrived in the 80th minute, with Raspadori setting up Leo Skiri Ostigard to head into the back of the net from inside the box to cap a difficult night for Rangers.