Christophe Galtier's side managed to avoid a third successive top-flight away defeat at the Stade de la Mosson, where Fabian Ruiz and Lionel Messi gave PSG a healthy two-goal cushion in the second half.
Arnaud Nordin curled home a delightful consolation for La Paillade, but the hosts were hit with a stoppage-time sucker punch as 16-year-old Warren Zaire-Emery completed the job for the visitors.
However, concern soon turned to star striker Mbappe, who endured nothing short of a nightmarish first half before coming off with a quarter of the game gone.
Prior to sustaining his injury, the 23-year-old was handed the chance to break the deadlock from the penalty spot in the first half, but his first effort was saved by Benjamin Lecomte.
Mbappe would seemingly be handed a reprieve when a retake was awarded, with Montpellier shot-stopper Lecomte shown to have been off his line following a VAR review.
The Frenchman went for the opposite corner on his second attempt, but the ball came back out off the post before he inexplicably sent the rebound high over the crossbar.
Injury was then added to insult for Mbappe, who stayed down after a tackle from Montpellier's Leo Leroy and gingerly walked off the field to be replaced by Hugo Ekitike.
PSG were already without Neymar on the night due to muscular fatigue - as well as the suspended Marco Verratti - and their injury situation went from bad to worse when Ramos was forced off not long after Mbappe.
Just after the half-hour mark, Ramos was involved in a nasty clash of heads with Montpellier attacker Stephy Mavididi, and he soon left the field amid fears of a suspected concussion.
While Ramos will seemingly recover from his issue relatively quickly, Mbappe is at risk of missing the first leg of PSG's Champions League last-16 tie against Bayern Munich on February 14.
Prior to their clash with the German champions - who defeated them 1-0 in the 2019-20 final - PSG also take on Toulouse and Monaco in Ligue 1 either side of a Coupe de France last-16 clash with Classique rivals Marseille.
Ramos and Mbappe are joined in the PSG infirmary by Nordi Mukiele, who is facing another couple of weeks out with a hamstring problem, while Presnel Kimpembe continues to be plagued by his Achilles injury.
PSG's win over Montpellier saw them extend their lead at the top of the Ligue 1 table to five points, with previous closest challengers Lens suffering a 1-0 defeat to Nice, allowing Marseille to leapfrog Les Sang et Or into second with victory over Nantes by two goals to nil.