Nadal, who has won the Monte Carlo Masters seven times in a row, started off brightly on the clay court by going a break up in the first until his Swiss opponent continued to hold his serve.
Despite executing a number of powerful shots, Wawrinka failed to push back the Spaniard, who wrapped up the opening set 7-5.
The 25-year-old continued his dominance in the second, displaying some precise shots to clinch a break up, while Wawrinka forced to stay in contention.
The world number 23 failed to overpower the Spaniard, who managed to edge the contest and snatch the victory.
Nadal will face either Jo-Wilfried Tsonga or Gilles Simon in the semi-finals.