Abstract The electrochemical CO 2 reduction reaction (eCO 2 RR) to multicarbon products has been widely recognized for Cu‐based catalysts. However, the structural changes in Cu‐based catalysts during the eCO 2 RR pose challenges to achieving an in‐depth understanding of the structure–activity relationship, thereby limiting catalyst development. Herein, we employ constant‐potential density functional theory calculations to investigate the sintering process of Cu single atoms of Cu−N−C single‐atom catalysts into clusters under eCO 2 RR conditions. Systematic constant‐potential ab initio molecular dynamics simulations revealed that the leaching of Cu−(CO) x moieties and subsequent agglomeration into clusters can be facilitated by synergistic adsorption of H and eCO 2 RR intermediates (e.g., CO). Increasing the Cu 2+ concentration or the applied potential can efficiently suppress Cu sintering. Both microkinetic simulations and experimental results further confirm that sintered Cu clusters play a crucial role in generating C 2 products. These findings provide significant insights into the dynamic evolution of Cu‐based catalysts and the origin of their activity toward C 2 products during the eCO 2 RR.