Background: Lateral compartmental osteoarthritis (LCOA), a major complication after medial mobile-bearing unicompartmental knee arthroplasty (UKA), is highly associated with the increased stress of the lateral compartment. This study aimed to analyze the effects on the stress and load distribution of the lateral compartment induced by lower limb alignment and coronal inclination of the tibial component in UKA through a finite element analysis. Methods: Eight three-dimensional models were constructed based on a validated model for analyzing the biomechanical effects of implantation parameters on the lateral compartment after medial Oxford UKA: postoperative lower limb alignment of 3 degrees valgus, neutral and 3 degrees varus, and the inclination of tibial components placed in 4 degrees, 2 degrees valgus, square, and 2 degrees and 4 degrees varus. The contact stress of femoral and tibial cartilage and load distribution were calculated for all models. Results: In the 3 degrees valgus lower limb alignment model, the contact stress of femoral (3.38 MPa) and tibial (3.50 MPa) cartilage as well as load percentage (45.78%) was highest compared to any other model, and was increased by 36.75%, 47.70%, and 27.63%, respectively when compared to 3 degrees varus. In the condition of a neutral position, the outcome was comparable for the different tibial tray inclination models. The inclination did not greatly affect the lateral compartmental stress and load distribution. Conclusions: This study suggested that slightly varus (undercorrection) lower limb alignment might be a way to prevent LCOA in medial mobile-bearing UKA. However, the inclination (4 degrees varus to 4 degrees valgus) of the tibial component in the coronal plane would not be a risk factor for LCOA in neutral position.