Optimal treatment of proximal humerus fractures remains controversial. Locking plates offer theoretical advantages but are associated with complications in the clinic. This study aimed to perform parametric design optimisation of proximal humerus plates to enhance their mechanical performance. A finite element (FE) model was developed that simulated a two-part proximal humerus fracture that had been treated with a Spatial Subchondral Support (S3) plate and subjected to varus bending. The FE model was validated against in vitro biomechanical test results. The predicted load required to apply 5 mm cantilever varus bending was only 0.728% lower. The FE model was then used to conduct a parametric optimisation study to determine the orientations of inferomedial plate screws that would yield minimum fracture gap change (i.e. optimal stability). The feasible design space was automatically identified by imposing clinically relevant constraints, and the creation process of each FE model for the design optimisation was automated. Consequently, 538 FE models were generated, from which the obtained optimal model had 4.686% lower fracture gap change (0.156 mm) than that of the manufacturer’s standard plate. Whereas its screws were oriented towards the inferomedial region and within the range of neck-shaft angle of a healthy subject. The methodology presented in this study promises future applications in patient-specific design optimisation of implants for other regions of the human body.