Abstract: Groundwater in the Panyang Lake Plain (a major part of the Middle and Lower Reaches Plain of the Yangtze River) was found to be polluted due to industrial pollutants, rural sewage and agricultural wastewater with the rapid development of urbanization. More and more areas of rural groundwater suffered from pollution. The pollution situations became increasingly worse. In order to acquire the information on groundwater heavy metal pollution in the Pangyang Lake Plain, on the basis of abundant regional hydrogeologic surveys and detections of water samples, the contents of heavy metals (Cu, As, Cr, Hg, Pb and Cd) in the groundwater are analyzed to understand the pollution status of heavy metals in groundwater in the Poyang Lake Plain, and the health risk assessment model of the United States Environmental Protection Agency (USEPA) is used to evaluate the health risk level. The results show that the contents of Cd, Cu, Hg, As, Pb and Cr in 171 groundwater samples in the study area change greatly, and the average contents of Hg and Cd exceed the III standard value of groundwater environmental quality (GB/T 14848—2017). It is found that the groundwater quality of the Poyang Lake Plain is mainly affected by human being and the local groundwater is seriously polluted. The results of carcinogen health risk assessment show that the average annual health risk values of Cr, As and Cd are greater than acceptable risk values, and the health risk value of Cr is the largest, Cd is the lowest, indicating that Cr is the key factor for carcinogens risk. The non-carcinogenic health risk levels of Hg, Pb and Cu are Hg>Pb>Cu, and their risk can be ignored. The health risk of regional drinking water is mainly affected by carcinogens factor, and in generally, men’ health risk is greater than that of women. This paper provides a theoretical basis for the research and management of groundwater quality pollution in the Poyang Lake plain area, and provides reference for the monitoring and quality control of heavy metals in other areas.