One of the major failure modes of bioprosthetic heart valves (BHVs) is noncalcific structural deterioration due to fatigue of the tissue leaflets; yet, the mechanisms of fatigue are not well understood. BHV durability is primarily assessed based on visual inspection of the leaflets following accelerated wear testing. In this study, we developed a computational framework to simulate BHV leaflet fatigue, which is both efficient and quantitative, making it an attractive alternative to traditional accelerated wear testing. We utilize a phenomenological soft tissue fatigue damage model developed previously to describe the stress softening and permanent set of the glutaraldehyde-treated bovine pericardium leaflets in BHVs subjected to cyclic loading. A parametric study was conducted to determine the effects of altered leaflet and stent elastic properties on the fatigue of the leaflets. The simulation results show that heterogeneity of the leaflet elastic properties, poor leaflet coaptation, and little stent-tip deflection may accelerate leaflet fatigue, which agrees with clinical findings. Therefore, the developed framework may be an invaluable tool for evaluating leaflet durability in new tissue valve designs, including traditional BHVs as well as new transcatheter valves.