The arch-rivals are separated by just 60 kilometres, and one position in the Ligue 1 table, with Saint-Etienne holding onto France's UEFA Europa League spot in fourth, three points ahead of fifth-placed Lyon.
Saint-Etienne will travel to the Stade de Gerland knowing a win will strike a significant blow in the race for a Europa League berth next season, while they could also draw level with Lille on 54 points if the club in third lose to Guingamp.
But according to Saint-Etienne's Turkish striker Mevlut Erding, bragging rights remain most important for the men in green.
"The derby is the most important," Erding told ONZEO.
"Before talking about the podium, we have the derby to play. We are focused only on this game because it is very important for the entire club and our supporters."
Saint-Etienne have not won the Derby du Rhone since 2010 when they triumphed 1-0 at Lyon's home ground but they will enter the game with improved confidence having defeated Sochaux 3-1 last week, breaking a two-match losing streak.
Lyon did the same last week, winning 1-0 at Guingamp to bounce back from consecutive losses, although Remi Garde's team have some key players out injured including Clement Grenier, Gueida Fofana, Mouhamadou Dabo and Miguel Lopes, while Yassine Benzia is suspended.
Christophe Galtier, Saint-Etienne's coach, will have to do without injured midfielder Romain Hamouma but will be thrilled his team found a way back onto the scoresheet against Sochaux with Erding scoring twice.
Ligue 1 leaders Paris Saint-Germain will begin the round on Friday with a trip to Nice.
PSG have won their past eight matches in all competitions, while 11th-placed Nice are unbeaten in three.
If Nice manage to upset PSG, second-placed Monaco will be poised to pounce as they travel to struggling Evian TG on Saturday.
Evian sit one spot above the relegation zone, while Monaco should enter the contest with plenty of confidence after destroying Lens 6-0 in their Coupe de France quarter-final on Wednesday.
In other fixtures involving relegation-threatened teams, Marseille will hope to end their four-game winless streak when they travel to second-last Sochaux, while bottom club Ajaccio host Toulouse and 18th-placed Valenciennes will visit Montpellier.
Resurgent Nantes will take on Bordeaux, Lorient are set to head east to Reims and Rennes host Bastia.
