Ruben "Cani" Garcia flicked a cross from Nilmar to put Villarreal ahead in the 45th minute.
Falcao equalized from the penalty spot in the 49th, and fellow Colombia international Freddy Guarin made it 2-1 in the 61st when he headed his rebound under goalkeeper Diego Lopez.
Radamel stabbed in Hulk's cross off a counterattack six minutes later, and the striker brought his competition-leading scoring total to 15 with headers in the 75th and 90th.
Porto will look to protect its comfortable margin in Spain next Thursday to set up an all-Portuguese final against Benfica or Braga.
Nini
