Monaco have been on fire under Leonardo Jardim this season, but will have to find a way past the 10-time winners at Stade Velodrome in the tie of the round.
Holders Paris Saint-Germain – winners in each of the last two years – are away to Ligue 2 team Chamois Niortais.
Aside from Marseille v Monaco, there were two other all-Ligue 1 fixtures drawn out of the hat, with Bordeaux to play at home against Lorient and Bastia to host Angers.
Two teams from the fourth tier made it to the last 16 and both were rewarded with home ties.
Bergerac take on top-flight side Lille, while EFC Frejus Saint-Raphael host second-tier Auxerre.
Matches will be played on February 28 and March 1.
Coupe de France last 16 draw: