Anaerobic digestion (AD) is a promising technology for renewable energy production from organic waste. In order to maximize the produced biogas quantity and quality, this paper deals with the optimization of the AD process in a CSTR bioreactor of a full-scale biogas plant. For this purpose, a novel approach was adopted coupling, a highly complex BioModel for AD simulation, and a gradient-based optimization method. In order to improve AD performance, the dosages of various types of biological additives, the dosages of inorganic additives, and the temperature in the bioreactor were optimized in three different scenarios. The best biogas quality was obtained using multi-objective optimization, where the objective function involves the following two conflicting objectives: the maximization of biogas production and minimization of the needed heating energy. The obtained results show that, potentially, the content of CH4 can be increased by 11%, while the contents of H2, H2S, and NH3 can be reduced by 30%, 20%, and 81% when comparing the simulation results with the experimental data. The obtained results confirm the usefulness of the proposed approach, which can easily be adapted or upgraded for other bioreactor types.