Guingamp came into the game off the back of an eight-game undefeated run in all competitions, but were beaten thanks to goals from Dimitar Berbatov and Anthony Martial, with Christophe Mandanne's dismissal compounding matters for the visitors at the Stade Louis II.
Berbatov's eighth-minute goal set Leonardo Jardim's men off on the right path - the Bulgarian heading home Yannick Ferreira-Carrasco's delivery - before Mandanne was sent off following a collision with Ricardo Carvalho.
Martial struck late on to settle the tie and end Guingamp's hopes, with Lille joining them in the last four later on Wednesday.
Rene Girard's men were 2-0 winners against fellow Ligue 1 side Nantes at the Stade Pierre Mauroy as the hosts kept a third consecutive clean sheet in all competitions.
Sebastien Corchia gave his side the lead just nine minutes in with a stunning curled effort from distance - the defender's first goal since July.
Lille's second was similarly impressive and came from another unlikely source, this time it was Simon Kjaer curling home a free-kick to put the tie beyond doubt.
Monaco will now face Bastia in the semi-finals and Lille take on holders Paris Saint-Germain.
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