Background: Deviations in knee joint geometry and alignment were previously related to an increased risk for knee OA. These were hypothesized to influence the load distribution over the articular cartilage. Therefore, this study evaluated the effect of altered knee joint geometry and alignment in the coronal and transverse plane on the medial–lateral load distribution and ligament strain using a musculoskeletal modeling approach. Methods: Joint kinematics during gait were measured in 15 healthy adults. Using different musculoskeletal models with altered geometry of the tibia plateau or knee joint malalignment in the coronal and transverse plane, the resulting muscle, ligament and contact forces were calculated. Next, the distribution of the load over the medial and lateral condyle was analyzed and compared to the reference loading distribution, with neutral geometry and alignment, using repeated-measures ANOVA and individual t-tests, with a Bonferroni-corrected alpha level. Results: Coronal plane malalignment significantly affected the load distribution. Small changes in coronal tibial slope had less pronounced effects on the load distribution, but increased ligament strains. Transverse plane malalignment only minimally affected the load distribution. Conclusion: Coronal plane knee malalignment affected knee loading, with increased varus alignment resulting in increased medial loading. This confirms a causal relation between coronal malalignment and increased medial compartment loading and suggests a potential role of aberrant coronal plane alignment on OA initiation. Altered coronal tibial slope induced increased ligament strains, potentially contributing to a cascade of knee laxity and subsequently more extreme knee malalignment.