With the dramatic increase in anthropogenic threats to the Pearl River Estuary (PRE), the population size of the Indo-Pacific humpback dolphins (Sousa chinensis) has significantly decreased over the past decade. To understand the impact and potential risks of intense human activities on these dolphins, factors related to the mortality of humpback dolphins in the PRE were investigated by a detailed examination of 343 dolphin specimens stranded during 2003–2017. There was a significant (p < 0.01) increasing trend for humpback dolphin stranding, reflecting the accelerating rate of the population decline. A large proportion of strandings (35.88%) were neonates. A low recruitment rate implies slow population growth, and hence, limited capacity to resist anthropogenic stress. The most commonly diagnosed causes of death were vessel collision and net entanglement. The concentrations of trace metals, polychlorinated biphenyl (PCB) congeners, dichlorodiphenyltrichloroethane, polycyclic aromatic hydrocarbons, and most of per- and polyfluoroalkyl substances (PFASs) in the dolphin samples were greater than those previously reported in cetaceans globally. Furthermore, Cu, PCB77, PCB169, PCB81, PCB37, and PFASs (excluding PFBA, PFPeA, PFHxA, PFHxDA, and PFODA) were the major pollutants accumulated in neonates. 67% of PCB, 78% of Cu, and 100% of perfluorooctane sulfonate concentrations in the neonates exceeded the threshold for toxicological effects in marine mammals, suggesting that these compounds could be important factors contributing to the low survival rate of calves in this area. This study revealed that vessel transportation, fishing activities, and pollutant bioaccumulation are the three major causes of humpback dolphin mortality in the PRE. These results highlight the need for more efforts to restrict anthropogenic activities, especially vessel traffic, the catching of these marine animals and fishing, and pollutant discharge, in order to prevent vulnerable species from continuous population decline and further extinction.