The patellofemoral joint plays a crucial mechanical role during walking and running. It increases the knee extensor mechanism’s moment arm and reduces required knee extension muscle forces to generate the extension moment that supports body weight, prevents knee buckling and propels the centre-of-mass. However, the mechanical implications of moment arm variation caused by patellofemoral and tibiofemoral motion remain unclear. We used a data-driven musculoskeletal model with a 12-degree-of freedom knee to simulate the knee extension moment arm during walking and running. Using a geometric method to calculate the moment arm, we found smaller moment arms during running than walking during the swing phase. Overall, knee flexion causes differences between running and walking moment arms as increased flexion causes a posterior shift in the tibiofemoral rotation axis and patella articulation with the distal femur. Moment arms were also affected by knee motion direction and best predicted by separating by direction instead of across the entire gait cycle. Furthermore, we found high inter-subject variation in the moment arm that was largely explained by out-of-plane motion. Our results are consistent with the concept that shorter moment arms increase the effective mechanical advantage of the knee and may contribute to increased running velocity.