The heavy-spending Ligue 1 side last won the tournament in 1991 and have a big opportunity to reach the final against their struggling hosts, who are in poor form
Claudio Ranieri's side are the favourites to win France's oldest domestic competition for a sixth time following a campaign that has seen them challenge Paris Saint-Germain for the Ligue 1 title in their first season back in the top flight.
Monaco, who won Ligue 2 last term, spent big in the close-season to bring in stars such as Radamel Falcao, James Rodriguez and Joao Moutinho, though their quest to win the French league crown appears set to fall short.
They last won the Coupe de France back in 1991 and came close to doing so again in the 2010 final, only to lose 1-0 to PSG.
Guingamp - promoted with Monaco and Nantes last campaign - head into the game in the midst of a woeful slump that has seen them slip to within five points of the Ligue 1 drop zone.
Jocelyn Gourvennec's team have won only four of their last 22 league matches and are yet to face a top-tier team in this season's Coupe de France.
But it is the Brittany club who have the most recent experience of winning the tournament, as they beat neighbours Rennes 2-1 in the 2009 final despite being a league below them, and a repeat of that final could be on the cards if Guingamp progress and Rennes overcome fellow second-tier Angers in their last-four clash.
However, the hosts are likely to be without two experienced players at the Stade du Roudourou, with midfielder Lionel Mathis (Achilles) and defender Reynald Lemaitre (calf) both expected to miss out.
Meanwhile, Monaco remain without Falcao (knee) while left-back Layvin Kurzawa is also sidelined as they aim to win a first major trophy since claiming the 2003 Coupe de la Ligue title.