The natural river system, which is inherently interconnected, is an essential resource for human and economic society. Beyond water, and the flows of substance (e.g. sediment, contaminant), energy (e.g. streamflow velocity), and information (e.g. livelihood and activity) are exchanged in an interconnected river system. However, under the joint influences of natural evolution and human activities, the natural river system has been and is being changed. Particularly, water-related human activities in recent years are frequent and highly intensified, such as the water allocation projects and man-made reservoirs. Therefore, research on the evaluation of human activities affecting the interconnected river system network (IRSN) is needed to technically support the relevant practices. This study analyzed the affecting factors of IRSN from two perspectives: natural perspective and social perspective. The processes of human activities affecting the IRSN were theoretically explained. On this basis, both the positive and negative influences of human activities on IRSN were summarized in three aspects: interconnected-river-system-network function relationship, rivers-lake-system natural function, and interconnected-river-system-network function. To this end, the study proposed a quantitative evaluation method to assess human activities affecting the IRSN in the above three aspects. As the Huaihe River basin was severely influenced by human activities, we applied the evaluation method in this basin. Results show that human activities contributed to the interconnected-river-system-network function, meaning that possible influences on water scarcity and flood protection were generated in improving the complexity of man-made river system. Meanwhile, slight negative influences on the rivers-lake-system natural function were reported, as downstream aquatic life and surrounding environment were affected by the flow changes of water, substance and information. Together with characteristics of the Huaihe River basin, the overall quantitative evaluation results suggested that stepping up the efforts to protect the environment could further positively influence the IRSN in the Huaihe River basin. This study sheds new light on our understanding and quantitative evaluation of the influence of human activities on the IRSN.