A central composite design circumscribed method was used to define the experimental conditions that improve the methane production rate (kCH4, liters of methane per kilogram of VS of waste added and per day) and the cumulative methane production (cMP, liters of methane per kilogram of VS of waste added) of the co-digestion of sewage sludge (SS) with crude glycerol (cGly) and waste frying oil (WFO). Three factors were selected, i.e., SS concentration, global co-substrate concentration, and mass fraction of cGly (xcGly) in a mixture of cGly and WFO (in chemical oxygen demand, COD). SS digestion without co-substrate reached a cMP of (294 ± 6) L·kg−1 and a kCH4 of (64 ± 1) L·kg−1·d−1, at standard temperature and pressure conditions and expressed relatively to the initial volatile solids. After statistical analysis, SS and co-substrate concentrations of 4.6 g·L−1 and 8.8 g·L−1 (in COD), respectively, with xcGly of 0.8, were defined to simultaneously boost cMP (91 % more) and kCH4 (3-fold increase). Application of these conditions would yield 214 MWh more in electricity per 1000 m3 of SS digested.