Cleft palate surgery most commonly results in palatal fistula, but this complication can also be observed in congenital malformations, palatal tumors, and autoimmune diseases. Palatal fistula repair is crucial in restoring everyday speech and swallowing function, improving patients’ psychological and social well-being. However, treating palatal fistula remains challenging for oral and maxillofacial surgeons. In addition, fabricating a palatal fistula prosthesis with a precise fit to the fistula using traditional techniques is hardly achievable in the design and production process. In recent years, digital technology has been increasingly applied in palatal fistula prosthesis fabrication. Based on computer fluid dynamics (CFD)-assisted design and three-dimensional printing technology, we developed a personalized palatal prosthesis made of light-cured polyurethane to repair palatal fistula and restore normal airflow during speech. Material property tests show that this light-cured polyurethane material has excellent hydrophilicity, mechanical properties, water resistance, and good rheological performance. The excellent biocompatibility of the polyurethane palatal prosthesis was confirmed in in vivo and in vitro experiments. The study results also indicate that CFD pre-analysis provides accurate guidance for palatal fistula design and future evaluation of outcomes. Therefore, CFD pre-analysis and additive manufacturing synergy provide a new treatment method. In combination with the excellent biocompatibility and mechanical properties of polyurethane, this study proposes a new strategy for treating refractory palatal fistula and extensive palatal defects, aiming to reduce the difficulty of prosthesis fabrication and maximize the restoration effect and quality of life for patients.