The multi-electron reduction of CO2 to hydrocarbons or alcohols is highly attractive in a sustainable energy economy, and the rational design of electrocatalysts is vital to achieve these reactions efficiently. Single-atom electrocatalysts are promising candidates due to their well-defined coordination configurations and unique electronic structures, which are critical for delivering high activity and selectivity and may accelerate the explorations of the activity origin at atomic level as well. Although much effort has been devoted to multi-electron reduction of CO2 on single-atom electrocatalysts, there are still no reviews focusing on this emerging field and constructive perspectives are also urgent to be addressed. Herein recent advances in how to design efficient single-atom electrocatalysts for multi-electron reduction of CO2, with emphasis on strategies in regulating the interactions between active sites and key reaction intermediates, are summarized. Such interactions are crucial in designing active sites for optimizing the multi-electron reduction steps and maximizing the catalytic performance. Different design strategies including regulation of metal centers, single-atom alloys, non-metal single-atom catalysts, and tandem catalysts, are discussed accordingly. Finally, current challenges and future opportunities for deep electroreduction of CO2 are proposed.