Since every structure in the human body can vary, customization is important to choose the most appropriate medical option according to the patient. Total knee arthroplasty (TKA) is a surgical procedure for the knee replacement that has a high rate of patient’s dissatisfaction. Indeed, conventional prostheses are based on anthropometric data that accommodate common knees. However, mismatch can occur due to anatomical variations among the individuals. Thanks to the advances in imaging techniques and 3D modeling, it is possible to create customized knee implants starting from medical images. In this context, the present research proposes a methodology to design a customized knee implant taking into account clinical (e.g., prosthesis alignment and surgical cuts) and technical parameters (e.g., materials) that have a direct impact on TKA performance and patient’s satisfaction. Changing these parameters, different scenarios have been modeled and simulated to understand the most suitable combination. Finite element analysis (FEA) has been employed to simulate and compare the proposed customized models, changing the different clinical and technical parameters. Stress induced by different combinations of the parameters has been evaluated to choose the optimal solution among the eight proposed scenarios. The optimum is reached with a physiological alignment, with six femoral facets and the ultra-high molecular weight polyethylene (UHMWPE) tibial insert. The implant design maintains the natural joint line and allows preserving more bone. The material is the parameter that mostly influences the stress distribution.