The carbon-water-food systems are inextricably linked and increasingly strained by climate change and human activities. However, there is a lack of studies that examine how climate and human activities affect the carbon-water-food interactions, particularly in large basin regions like the Yangtze River Basin (YZRB) of China. This study addresses this gap by quantifying the carbon-water-food systems through key ecosystem services-carbon storage (CS), water yield (WY), and food production (FP)-using the InVEST model, investigate the synergies and trade-offs among these systems both at the basin-wide scale and across the nine sub-basins within the YZRB. Furthermore, Random Forest (RF) and Partial Least Squares Structural Equation Modelling (PLS-SEM) are employed to conduct a comprehensive analysis of how climate and human activities influence the interactions among the carbon-water-food systems. The results showed that: (1) During the study period from 2000 to 2020, the total of CS decreased by 56.53 × 10