The effects of tennis racket grip size on the forces exerted by muscles affecting lateral epicondylalgia (LE) were assessed in this study. Grip forces and joint moments applied on the wrist were quantified under three different handle size conditions, with and without induced muscle fatigue for intermediate and advanced players. The obtained experimental results were then used as input data of a biomechanical model of the hand. This simulation aimed to quantify the impact of grip strength modulation obtained in the experiment on the wrist extensor muscle forces. Our results show that there is an optimal grip diameter size defined as the handle inducing a reduced grip force during the stroke, in both fatigued and non-fatigued sessions. The results of the simulation suggested that extensor muscles were highly employed during forehand strokes, which confirms that the mechanical overuse of extensor tendons is a potential risk factor for tennis elbow occurrence. The handle grip size appeared to be a significant factor to reduce this extensor tendon loading. This suggests that grip size should be taken into account by players and designers in order to reduce the mechanical risk factors of overuse injury occurrence.