Claudio Ranieri's men sit top of the Ligue 1 table and are undefeated after the first five games, with star striker Radamel Falcao already finding the net on four occasions.
However, the principality club have not won a major trophy since 2003, when they beat Sochaux 4-1 in the Coupe de la Ligue final, and they will start their quest to regain the crown against a Reims side that has lost just once so far this season.
Rennes, who reached last year's final only to lose to Saint-Etienne, host Ligue 2 Nancy, while Brittany rivals Nantes and Lorient face-off at the Stade de la Beaujoire.
Bastia have been drawn against Corsican neighbours Ajaccio, Lille take on Auxerre, and 2011-12 Ligue 1 winners Montpellier travel to Sochaux.
Elsewhere, Valenciennes meet Troyes, Guingamp face Evian, Toulouse take on Creteil and Tours play Amiens
UEFA Champions League qualifiers PSG and Marseille do not enter the competition until the round of 16, along with Lyon, Saint-Etienne, Nice and Bordeaux.
The third-round ties are to be played on October 29-30.
