The fatigue damage to polymers generally depends on the material properties as well as on the mechanical, thermal, chemical, and other environmental influences. In this article, a methodology for modeling the dependence of the PA66 S-N curves on the material parameters, the material state, and the operating conditions is presented. The core of the presented methodology is a multilayer perceptron neural network combined with an analytical model of the PA66 S-N curve. Such a hybrid approach simultaneously utilizes the good approximation capabilities of the multilayer perceptron and knowledge of the phenomenon under consideration, because the analytical model for the S-N curves was estimated on the basis of the existing experimental data from the literature. The article presents the theoretical background of the applied methodology. The applicability and uncertainty of the presented methodology were assessed for the available data from the literature. The results show that it was possible to approximate the PA66 S-N curves for different input parameters if the space of the input parameters was adequately covered by the corresponding S-N curves.