Although it is well known that fatigue can greatly reduce muscle forces, it is not generally included in biomechanical models. The aim of the present study was to develop an electromyographic-driven (EMG-driven) biomechanical model to estimate the contributions of flexor and extensor muscle groups to the net joint moment during a nonisokinetic functional movement (squat exercise) performed in nonfatigued and in fatigued conditions. A methodology that aims at balancing the decreased muscle moment production capacity following fatigue was developed. During an isometric fatigue session, a linear regression was created linking the decrease in force production capacity of the muscle (normalized force/EMG ratio) to the EMG mean frequency. Using the decrease in mean frequency estimated through wavelet transforms between dynamic squats performed before and after the fatigue session as input to the previous linear regression, a coefficient accounting for the presence of fatigue in the quadriceps group was computed. This coefficient was used to constrain the moment production capacity of the fatigued muscle group within an EMG-driven optimization model dedicated to estimate the contributions of the knee flexor and extensor muscle groups to the net joint moment. During squats, our results showed significant increases in the EMG amplitudes with fatigue ( in average) while the outputs of the EMG-driven model were similar. The modifications of the EMG amplitudes following fatigue were successfully taken into account while estimating the contributions of the flexor and extensor muscle groups to the net joint moment. These results demonstrated that the new procedure was able to estimate the decrease in moment production capacity of the fatigued muscle group.