Background: Fatigue failure of artificial leaflets significantly limits the durability of prosthetic valves. However, the costs and complexities associated with in vitro testing and conventional clinical trials to investigate the fatigue life of leaflets are progressively escalating. In silico trials offer an alternative solution and validation pathway. This study presents in silico trials of prosthetic valves, along with methodologies incorporating nonlinear behaviors to evaluate the fatigue life of artificial leaflets. Methods: Three virtual patient models were established based on in vitro test and clinical trial data, and virtual surgeries and physiological homeostasis maintenance simulations were performed. These simulations modeled the hemodynamics of three virtual patients following transcatheter valve therapy to predict the service life and crack propagation of leaflets based on the fatigue damage assessment. Results and Conclusions: Compared to traditional trials, in silico trials enable a broader and more rapid investigation into factors related to leaflet damage. The fatigue life of the leaflets in two virtual patients with good implantation morphology exceeded 400 million cycles, meeting the requirements, while the fatigue life of a virtual patient with a shape fold in the leaflet was only 440,000 cycles. The fatigue life of the leaflets varied considerably with different implant morphologies. Postoperative balloon dilation positively enhanced fatigue life. Importantly, in silico trials yielded insights that are difficult or impossible to uncover through conventional experiments, such as the increased susceptibility of leaflets to fatigue damage under compressive loading.