A biomechanical model was developed to simulate the selective effect of the co-contraction force provided by each hamstring muscle on the shear and compressive tibiofemoral joint reaction forces, during open kinetic-chain knee-extension exercises. This model accounts for instantaneous values of knee flexion angle [Formula: see text], angular velocity and acceleration, and for changes in magnitude, orientation, and application point of external resistance. The tibiofemoral shear force (TFSF) largely determines the tensile force on anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL). Biceps femoris is the most effective hamstring muscle in decreasing the ACL-loading TFSF developed by quadriceps contractions for [Formula: see text]. In this range, the semimembranosus generates the dominant tibiofemoral compressive force, which enhances joint stability, opposes anterior/posterior tibial translations, and protects cruciate ligaments. The semitendinosus force provides the greatest decreasing gradient of ACL-loading TFSF for [Formula: see text], and the greatest increasing gradient of tibiofemoral compressive force for [Formula: see text]. However, semitendinosus efficacy is strongly limited by its small physiological section. Hamstring muscles behave as a unique muscle in enhancing the PCL-loading TFSF produced by quadriceps contractions for [Formula: see text]. The levels of hamstrings co-activation that suppress the ACL-loading TFSF considerably shift when the knee angular acceleration is changed while maintaining the same level of knee extensor torque by a concurrent adjustment in the magnitude of external resistance. The knowledge of the specific role and the optimal activation level of each hamstring muscle in ACL protection and tibiofemoral stability are fundamental for planning safe and effective rehabilitative knee-extension exercises.