Falcao's goals took him to a record 16 in the competition, beating Jurgen Klinsmann's total of 15 for Bayern Munich in the 1995/95 competition when it was the UEFA Cup.
With Porto set fair for the final in Dublin in May, they will be joined there by another Portuguese club, with Benfica holding a slight edge over Sporting Braga after beating them 2-1 at home also on Thursday.
Villarreal - who were only in this season's competition because Real Mallorca were disqualified from competing because they didn't meet financial regulations set by UEFA - had looked to be in control at the break after Cani had put them ahead.
However, whatever Andre Villas-Boas, the hottest managerial property around, said at half-time it transformed his side and within minutes they were level as 25-year-old Falcao went down in the area and got up to convert the resulting penalty.
Falcao's fellow Colombian Freddy Guarin then gave them the lead in the 61st minute as he cut in superbly from the left, saw his shot come back off the post but he reacted brilliantly to head home the rebound.
From them on it was all Falcao as he tucked home the third in the 67th minute after great work by strike partner Hulk, who had a quiet night himself in front of goal just going close with one rasping shot from outside the area in the first-half.
Falcao - named after the great Brazilian midfielder of the 1980's who was part of the thrilling 1982 World Cup side - rounded off the scoring with two headers the first a superb diving effort and the final one saw him rise above the stunned Villarreal defence in the dying seconds.
With almost both feet firmly in the May 18 final, 33-year-old Villas-Boas, who learnt a lot from former Porto handler Jose Mourinho though they have since fallen out, is on course for delivering a treble as Porto are also in the doemstic cup final.
His overall record with Porto since he took over is 45 victories and just three defeats in 52 matches.
Benfica - who are second in the league a massive 19 points behind Porto - and Braga's clash only really came alive for 10 minutes in the second-half.
The hosts took the lead in the 50th minute as Jardel reacted quickest when Paraguayan striker Oscar Cardozo's header from Maxi's brilliant cross came back off the bar.
However, Braga - who enjoyed a decent maiden campaign in the Champions League which included a home win over Arsenal in the group stage - levelled shortly afterwards as Vandinho came up with a towering header that gave the 'keeper no chance.
Benfica, though, restored their one goal advantage just before the hour mark as the giant Cardozo showed he has more finesse to his game than just heading power when he stroked home a brilliant left footed freekick which curled into the top corner.
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