Important activities of daily living, like walking and stair climbing, may be impaired by muscle weakness. In particular, quadriceps weakness is common in populations such as those with knee osteoarthritis (OA) and following ACL injury and may be a result of muscle atrophy or reduced voluntary muscle activation. While weak quadriceps have been strongly correlated with functional limitations in these populations, the important cause–effect relationships between abnormal lower extremity muscle function and patient function remain unknown. As a first step towards determining those relationships, the purpose of this study was to estimate changes in muscle forces and contributions to support and progression to maintain normal gait in response to two sources of quadriceps weakness:​ atrophy and activation failure. We used muscle-driven simulations to track normal gait kinematics in healthy subjects and applied simulated quadriceps weakness as atrophy and activation failure to evaluate compensation patterns associated with the individual sources of weakness. We found that the gluteus maximus and soleus muscles display the greatest ability to compensate for simulated quadriceps weakness. Also, by simulating two different causes of muscle weakness, this model suggested different compensation strategies by the lower extremity musculature in response to atrophy and activation deficits. Estimating the compensation strategies that are necessary to maintain normal gait will enable investigations of the role of muscle weakness in abnormal gait and inform potential rehabilitation strategies to improve such conditions.