Background <p>Given that chronic ankle instability (CAI) changes lower extremity biomechanics, potentially leading to greater joint loading, understanding the link between these biomechanical changes and joint loading is critical to identifying early degenerative changes. We aim to compare knee joint contact force (JCF) generated during running between patients with CAI and controls and identify the lower extremity muscles that contribute to these forces.</p> Methods <p>Twelve patients with CAI and 12 controls performed a running task. A musculoskeletal simulation was employed to estimate the compressive, mediolateral and anteroposterior forces on the tibiofemoral joint. Contributions of the lower extremity muscles and GRF to these forces were also analyzed. One-dimensional statistical parametric mapping and independent t-tests were performed for analysis.</p> Results <p>Patients with CAI demonstrated greater posterior and medial knee shear force than controls during running (<i>p</i> &lt; 0.05). Compressive impulse was higher (<i>p</i> = 0.045), but peak compressive force did not differ (<i>p</i> &gt; 0.05). The greater knee JCF in patients with CAI was primarily driven by greater quadriceps muscles (<i>p</i> &lt; 0.05).</p> Conclusions <p>Compared with the controls, the greater knee joint loading in patients with CAI results from greater quadriceps muscle contributions. These findings highlight the biomechanical link between ankle and knee joint health, suggesting that rehabilitation strategies addressing proximal muscle coordination may help reduce knee joint loading in patients with CAI.</p>