A chemo-mechanical model has been developed for predicting the long-term mechanical behavior of EPDM rubbers in a harsh thermal oxidative environment. Schematically, this model is composed of two complementary levels: The “chemical level” calculates the degradation kinetics of the macromolecular network that is introduced into the “mechanical level” to deduce the corresponding mechanical behavior in tension. The “chemical level” is derived from a realistic mechanistic scheme composed of 19 elementary reactions describing the thermal oxidation of EPDM chains, their stabilization against oxidation by commercial antioxidants but also by sulfide bridges, and the maturation and reversion of the macromolecular network. The different rate constants and chemical yields have been determined from a heavy thermal aging campaign in air between 70 and 170 °C on four distinct EPDM formulations: additive free gum, unstabilized and stabilized sulfur vulcanized gum, and industrial material. This “chemical level” has been used as an inverse resolution method for simulating accurately the consequences of thermal aging at the molecular (concentration changes in antioxidants, carbonyl products, double bonds, and sulfide bridges), macromolecular (concentration changes in chain scissions and cross-link nodes), and macroscopic scales (weight changes). Finally, it gives access to the concentration changes in elastically active chains from which are deduced the corresponding changes in average molar mass MC between two consecutive cross-link nodes. The “mechanical level” is derived from a modified version of the statistical theory of rubber elasticity, called the phantom network theory. It relates the elastic and fracture properties to MC if considering the macromolecular network perfect, and gives access to the lifetime of the EPDM rubber based on a relevant structural or mechanical end-of-life criterion. A few examples of simulations are given to demonstrate the reliability of the chemo-mechanical model.