The Argentine made light of the absence of Karim Benzema with a terrific treble as Jose Mourinho's men proved too good for their Catalan opponents.
Madrid, like Barcelona, was playing in black, and just as the club's arch-adversary had done earlier in the evening in Gijon, the capital club secured a hard-fought away success.
Higuain was in for the injured Benzema, one of a number of sidelined stars for coach Jose Mourinho, who was also missing Pepe, Ricardo Carvalho, Fabio Coentrao and long-term absentee Nuri Sahin.
Espanyol fell behind as Ronaldo received the ball from Kaka and set up Higuain on a quick counterattack, which the Argentine culminated by crashing a powerful right-footed angled drive into the top corner 17 minutes in.
Espanyol looked lively despite going behind and Iker Casillas made a fine save to deny Sergio Garcia, but it was all over as a contest as Higuain struck a brilliant second midway through the second period. The striker latched onto Alvaro Arbeloa's ball and lashed an unstoppable right-footed drive into the top right corner.
Home fans then applauded as former hero Jose Callejon was introduced as a substitute late in the game, but just five minutes later the summer signing had hurt his old club by finishing off a quick move after being set up by Ronaldo.
Higuain made it 4-0 in added time following a mistake from Hector Moreno to put a gloss on the scoreline and make it a night to remember for the Argentine and Madrid, which now has 13 points - one less than Barcelona.