Many previous studies lack sufficient quantitative evidences about changes in biomechanical properties of the knee in response to proximal fibular osteotomy (PFO). Therefore, the aim of this study was to compare the preoperative and postoperative effects of PFO on mechanical stresses in the knee joint and provide with a biomechanical basis for PFO in the treatment of mild knee osteoarthritis (KOA) with varus deformity. A total of 10 patients suffering mild KOA with varus deformity were enrolled in this study. Their image data from computerized tomography (CT) and magnetic resonance imaging (MRI) were used for finite element models, and PFO models were established. Static structural analysis was carried out using ABAQUS to compare the von Mises stress distribution and values of the maximal von Mises stress of femoral cartilage, meniscuses, tibial cartilages, and tibial plateau before and after surgery. The stress distribution in the cortical bone of the tibial plateau showed that stresses were transferred from the anterior medial area to the posterior medial area after PFO. Values of the maximal von Mises stress in femoral cartilage, medial meniscus, medial tibial cartilage, and tibial plateau after surgery were significantly lower than the preoperative values, with statistically significant differences (P < 0.05). Postoperative values of the maximal von Mises stress of lateral meniscus and lateral tibial cartilage were significantly higher than the preoperative ones, with statistically significant differences (P < 0.05). PFO could reduce the stresses in the medial compartment of the knee joint with stress pathways transferring from the anterior medial area to the posterior medial area of the tibial plateau. Therefore, PFO is recommended for the treatment of mild KOA with varus deformity featuring favorably pain-relieving effects.