Characterizing the regional intensity of human activities is an important scientific issue. In this study, the pole-axis spatial system (central places and roads of multiple grades, such as city, county, farm, and village and railway, highway, national road, provincial road, municipal road, county road, and town road) and central place theory were adopted to represent the spatial agglomeration characteristics of regional human activities as direct risk source of wetlands. Soil erosion and non-point source (NPS) pollution indicating indirect effects of human activities on wetlands at the regional scale were also considered. Based on these results, the regional ecological risk assessment (RERA) framework of wetlands was established. Using this wetland RERA framework, the spatial heterogeneity of risk grades in the Sanjiang Plain area was analyzed. The results show that: 1) The Defense Meteorological Program Operational Line-Scan System (DMSP/OLS) nighttime light intensity data and multiple level roads data could be used to delineate the regional "pole-axis" system and characterize the direct risk source of wetlands stemming from human activities at the regional scale. High and very high risk source intensity areas matched well with the regional pole-axis system, especially with the central places and roads of high grades. 2) Owing to its high ecological capital value per unit area and vulnerability, wetlands had highest risk. 3) The low, medium, high, and very high risk areas accounted for 64.00%, 24.28%, 10.38%, and 1.34% of the study area, respectively. 4) Overall, the southern parts of the Sanjiang Plain had higher risk levels than the northern parts. With regard to the management of regional ecological risk of wetlands, our recommendations include emphasizing the spatial relationship (location, direction, and so on) between wetlands and the regional pole-axis system in order to control direct risks of wetlands from human activities, and tradeoff and synergy between wetlands and other ecosystems (rainfed cropland, rice field, and forest land) through prevention and control of soil erosion and NPS pollution stemming from non-wetland areas in order to reduce the risk level of wetlands at the regional scale.