Converting CO2 into valuable chemicals has been intensively explored in recent years. Benefited from the substantial cost reduction of renewable electricity, the electrochemical methods have been emerging as a potential means for CO2 capture and conversion. Recently, molecular tuning has been recognized as a powerful technique to modify catalyst’s surface and verified effective in improving CO2RR performance. However, there are few comprehensive and insightful reviews on molecularly modified Cu-based catalysts to precisely modulate the activity and selectivity of C2+ products in CO2 reduction. Herein, the development of CO2RR plausible reaction mechanisms is first introduced. The process and reaction pathways of the carbon-carbon coupling are briefly discussed. Four main aspects of the molecular tuning strategy of the CO2RR are described as the first coordination layer, second coordination layer, outer-layer, and confined effects. The understanding of the improved C2+ performance is demonstrated for molecularly modified Cu-based catalysts. The challenges and perspectives in this field are addressed to further inspire the disclosure of the fundamental understanding in CO2RR, the system optimization, advanced in situ and operando techniques, and integration of CO2 capture and conversion technology with high activity and selectivity for durable applications.