The effect of compression on the chemical degradation of Nafion is investigated. Results indicate a nonlinear dependence of chemical degradation on compression level, with a slight decrease at 1 MPa and then increase up to 10 MPa. The results confirm the synergistic nature of mechanical effects on chemical fuel-cell membrane degradation, which are expected to occur in operando. The impact of compression is also shown to change the nano-domain structure, consistent with the increase in chemical decomposition. Thus, deformation energy accumulated in the membrane due to mechanical loads seemingly accelerates the chemical reactions driving the decomposition of the polymer membrane.