Abstract: The contradiction between China’s economic development and the protection of natural resources and the environment remains prominent. Reducing the damage and impact of economic activities on the natural resources and the environment through the scientific optimization of the organization structure and spatial layout of human activities is an important research topic in geography.Based on network externalities, this study focused on inter-regional economic correlations and their impact on the resources and environmental pressures, and explored the internal formation mechanism to break through physical boundaries. This study aimed to better understand the impact of spatial organization modes on resource use and environmental pressure. This paper examined the connection between county-level economic spatial networks and eco-efficiency exemplified in Jiangsu Province. The findings were as follows: (1) County-level eco-efficiency demonstrated fluctuations with an upward trend and showed zone differences, with higher eco-efficiency levels in municipal districts than other counties. (2)Spatial correlations among the county’s economy became increasingly tight, while connectivity, accessibility, and stability were continuously improved. However, the spatial correlation and interaction level remained weak. The spatial distribution characteristics indicated that point degree centrality, proximity centrality, and intermediate centrality were higher in the south and lower in the north, with an increase in mean value and range over time. (3) It was found that increases in network density and correlation degree, and decreases in average path length and network efficiency could improve overall ecological efficiency. Point centrality degree might promote local county and overall ecological efficiency. Proximity to the center could enhance local ecological efficiency but might hinder improvements in other counties and overall ecological efficiency. Meanwhile, intermediate centrality could raise the ecological efficiency of the local county, other counties, and the entire region. The impact of the county economic spatial network on eco-efficiency mainly came from the spillover effects in the network externality of the county economic spatial network. This study demonstrated the close relationship between county-level economic spatial networks and eco-efficiency. The economic spatial networks affected ecological efficiency through the attributes of nodes and edges. The centrality and externality of economic spatial networks jointly influenced eco- efficiency. Based on the findings of this study, relevant policy recommendations were proposed.