In the framework of sustainable development, there is an increasing need to assess, model, and optimize the implementation of renewable energy technologies such as the anaerobic co-digestion of different organic residues. This work studied the influence of some independent parameters on the production of biogas through anaerobic co-digestion of specific organic residues widely available in Colombia (pig manure -PM-, sewage sludge –SS–, organic fraction of municipal solid waste -OFMSW-, residues from the bottled fruit drinks industry -RBFDI-, and cocoa industry residue -CIR-). The Biochemical Methane Potential (BMP) of different mixtures was assessed through a Box-Behnken experimental design, where the parameters were: volatile solids content (0.5, 1.25 and 2 g VS), C/N ratio (25, 35 and 45), and nitrogen source (0% for only SS, 50% both residues PM and SS, and 100% if only PM). The results allowed empirical model building by using second-order polynomial and MARSplines. According to the maximization, the best mixture for biogas production is the one containing RBFDI, OFMSW, and SS, a C/N ratio of 40 and 0.5 g VS; the estimated production was around 382.17 ml CH4 g-1 VS, MARSplines demonstrated to have the best predictions values and the highest determination coefficient (94–97%). Moreover, it was evidenced that the content of g VS is a critical variable on the methane production, C/N ratio must be in average values, and both nitrogen sources are suitable to be used in the co-digestion process depending on the availability of the area of interest.