Structural changes in ligaments, particularly reduced stiffness, contribute to increased knee joint laxity in osteoarthritis (OA) patients. In silico modeling offers a valuable method to systematically assess how OA-related ligament alterations affect knee kinematics and contact mechanics. Understanding these effects requires considering OA-specific variations in joint geometry, alignment, and gait patterns. A previously developed musculoskeletal modeling workflow was used to incorporate common KOA-related anatomical variations and gait pattern variations. A probabilistic simulation approach assessed the impact of ligament-induced joint laxity on medial compartment loading. Ligament stiffness and reference strains were modeled as independent Gaussian distributions, centered at nominal model stiffness (−20%) and slack length (+20%), with standard deviations set at 5% based on literature-reported values. Increased medial compartment loading at the second peak occurred when posterior tibial translation and external tibial rotation were combined with either:​ (1) a gait pattern involving decreased ankle dorsiflexion and hip external rotation, increased foot eversion, and knee extension, or (2) a gait pattern with increased lumbar extension, trunk ipsilateral side bending, hip internal rotation, and knee internal rotation. These conditions also resulted in the largest shift in the center of pressure. While both anatomical variations and gait patterns influence knee joint loading, ligament stability plays a key role in determining medial compartment loading magnitude and location. These findings highlight the need to monitor ligament constraints in rehabilitation and computational models to develop personalized interventions that minimize excessive joint stress and slow disease progression.