Medial Tibial Stress Syndrome MTSS is frequently diagnosed as a severe clinical issue which occurs due to the cycle loadings (fatigue failure). Since the mechanical properties of the bones are random variables, therefore, there is a need for a probabilistic approach to rationally assess the reliability level of the fatigue failure of the tibia. The main contribution of this paper is to introduce a novel limit state function to determine the fatigue damage state and the reliability index of MTSS based on the different loading and aging conditions. In this study, the tibias of the several people at the different ages are subjected to the fatigue loadings. The load carrying capacities of the considered specimen are determined based on the reliability analysis. Indeed, several 3D finite element analyses are performed to find out the damage states of the tibias. Accordingly, the reliability-based stress analysis is accomplished to localize the most vulnerable zone of the bone. As it was expected, the higher loading cycles associated with the elder bones is related to the lowest fatigue reliability level. Finally, the target reliability level of MTSS is proposed to deliberate the safe level of the loading condition on the tibia in terms of the walking distance.