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The potential of co-digestion mixing thickened secondary sludge (TS) from extended aeration wastewater treatment plant and locally available substrates (whey, grease and septage) has been studied in this work, using three steps. The first step was a batch test to determine the biological methane potential (BMP) of different mixtures of the three co-substrates with TS. The second step was carried out with lab-scale reactors (20 L), simulating anaerobic continuous stirred tank reactors, fed by three mixtures of co-substrates that were determined according to the previous step results. Modeling was applied in the third step, using ADM1 as a mechanistic model to help understand the co-digestion process. According to the BMP step, septage used as a co-substrate has a negative effect on performance, and the addition of 10–30% grease or whey would lead to a gain of around 60–70% in the production of methane. The results from the reactor tests did not validate the positive effects observed with the BMP assay but confirmed good biodegradation efficiency (&gt, 85%). The main purpose of co-digestion in this scenario is to recover energy from waste and effluents that would require even more energy for their treatment. The protein and lipid percentages of particulate biodegradable COD are important variables for digester stability and methane production, as predicted by modeling. The results of simulations with the ADM1 model, adapted to co-digestion, confirmed that this model is a powerful tool to optimize the process of biogas production.