Anaerobic digestion is a highly complex process, particularly in co-digestion between poorly-defined, complex co-substrates like distillery wastewater, molasses, and crude glycerine. Thus, in this article, the authors tackled the problems by using Monod two-substrate with an intermediate (M2SI) model to represent accumulated biomethane evolution (ABE) obtained from the co-substrates, including easily degradable, slowly degradable substrates and intermediate. The M2SI model predictions were compared with the traditional Monod model's simulation results to clarify an outstanding of the present model in the aspect of modeling and control. Different behaviors of ABE curves from batch experiments were used to calibrate the M2SI model prediction with sensitivity analysis of the model parameters. It was found that the M2SI model gives a correct trend to describe the co-digestion process with multiple substrates and complex microbial activities with satisfactory fitting accuracy. At the same time, simple Monod kinetics have a good fit for dilute pure distillery wastewater, but the estimated microbial growth kinetics was counterintuitive. Therefore, M2SI Model has a broader range of applications for co-digestion dealing with the complexity of multiple microbial activities to consume inherently complex or artificial co-substrates.