Fuel cells are key elements in the transition to clean energy thanks to their neutral carbon footprint, as well as their great capacity for the generation of electrical energy by oxidizing hydrogen. However, these cells operate under straining conditions of temperature and humidity that favor degradation processes. Furthermore, the presence of hydrogen—a highly flammable gas—renders the assessment of their degradations and failures crucial to the safety of their use. This paper deals with the combination of physical knowledge and data analysis for the identification of health indices (HIs) that carry information on the degradation process of fuel cells. Then, a failure prognosis method is achieved through the trend modeling of the identified HI using a data-driven and updatable state model. Finally, the remaining useful life is predicted through the calculation of the times of crossing of the predicted HI and the failure threshold. The trend model is updated when the estimation error between the predicted and measured values of the HI surpasses a predefined threshold to guarantee the adaptation of the prediction to changes in the operating conditions of the system. The effectiveness of the proposed approach is demonstrated by evaluating the obtained experimental results with prognosis performance analysis techniques.