Analytical models that predict modulus degradation in cortical bone subjected to uniaxial fatigue loading in tension and compression are presented. On the basis of experimental observations, damage was modeled as self‐limiting for tension but not for compression. These mechanistic uniaxial damage models were then developed into a model for flexural fatigue of cortical bone based on laminated beam theory. The unknown coefficients in the uniaxial damage models were obtained by successfully fitting the resulting equations to uniaxial fatigue data from the literature on human cortical bone in tension and compression. Then, the predictions of the flexural model for the behavior of human cortical bone were compared with experimental results from a small but independent set of specimens tested at three different ranges of load in our laboratory. The behavior of the modulus degradation curves and the flexural fatigue lives of the specimens were in excellent agreement with the predictions of the model.