Abstract In fuel cell based combined heat and power (CHP) plants, degradation within the fuel cell stack and the steam methane reformer significantly affects the generated electrical and thermal power. As a consequence, incorporating system’s degradation within the model of the plant could be of great importance in order to estimate the resulting variations in the electrical and thermal power generation and taking appropriate measures to mitigate such deviations. To this end, in the present article, a multi-objective optimization approach has been proposed and employed to find the optimal operating parameters of an HT-PEM fuel cell based micro-CHP system within the first 15,000 h of operation while considering the impact of degradation. Two different optimization procedures with the following objective functions have been applied: (I) net electrical efficiency and thermal generation; and (II) net electrical efficiency and electrical power generation. Steam to carbon ratio, auxiliary to process fuel ratio, fuel partialization level and anodic stoichiometric ratio are the design parameters. Based on the results of optimization procedure I, the highest achievable net electrical efficiency at the beginning of operation is 32.75% which, due to degradation, considerably declines to 29.51% in the last time interval. Moreover, in all time steps, optimal solutions cover a wide domain of thermal generation which assures the capability of the system to easily cope with the thermal demand of the user. On the other hand, optimization procedure II displays a steady decrease in both electrical efficiency and electrical generation through time which indicates the adverse effect of degradation on these two performance indices. Finally, it has been found that, using optimization procedure I, the cumulative average electrical efficiency of the plant improved from 26.03% at normal operation to 27.56% at optimized condition. Furthermore, it was determined that by employing the optimal points obtained in optimization procedure II, the average cumulative electrical power generation is increased from 25.4 kW (at normal operation) to 26.8 kW. It is noteworthy that, the study not only provides some insights into the long-term performance of such system, but can be more importantly perceived as a guideline to adaptively optimize the operating conditions of the system in order to alleviate the degradation’s effect and to guarantee optimal performance of the system throughout its lifetime.