Tissue-engineered heart valves (TEHVs) are promising valve replacements due to their potential to regenerate into living heart valves, capable of growth and adaptation. Previous TEHVs showed promising results, but often developed progressive leaflet retraction in the long term. In a prior proof-of-concept study, we demonstrated that a novel geometry with more native-like mechanical behavior could give rise to more adaptive remodeling, thereby minimizing leaflet retraction in vivo. In the current study, we aimed to systematically analyze the impact of TEHV geometry on in vivo remodeling under both pulmonary and aortic conditions. Using a bio-inspired in silico framework, we predicted cell-driven, mechano-mediated remodeling in TEHVs post-implantation. Two parameterized valve designs were evaluated under both pulmonary and aortic pressure conditions. The results indicate that a valve design with smooth leaflets, a curved belly profile, and medium to wide attachment edge effectively minimizes stress concentrations and reduces the risk of valve insufficiency in both conditions. Additionally, this design should be tailored to specific hemodynamic conditions to prevent retraction in pulmonary applications and excessive stress concentrations in aortic applications. These insights provide essential guidelines for optimizing TEHV designs, aiming to promote functional remodeling and maintain valve functionality over time, thereby advancing the development of next-generation TEHVs with enhanced long-term outcomes.