Electrochemical CO 2 reduction reaction (eCO 2 RR) is of great significance to energy and environmental engineering, while fundamental questions remain regarding its mechanisms. Herein, we formulate a fundamental understanding of the interplay between the applied potential ( U ) and kinetics of CO 2 activation in eCO 2 RR on Cu surfaces. We find that the nature of the CO 2 activation mechanism in eCO 2 RR varies with U , and it is the sequential electron-proton transfer (SEPT) mechanism dominant at the working U but switched to the concerted proton-electron transfer (CPET) mechanism at highly negative U . We then identify that the barrier of the electron-transfer step in the SEPT mechanism exhibits an inverted region as U decreases, which originates from the rapidly rising Pauli repulsion in the physisorption of CO 2 with decreasing U . We further demonstrate catalyst designs that effectively suppress the adverse effect of Pauli repulsion. This fundamental understanding may be general for the electrochemical reduction reactions of closed-shell molecules.