Heavy metals are highly persistent in water and have a particular significance in ecotoxicology. Heavy metals loading from the Pearl River are likely to cause significant impacts on the environment in the South China Sea and the West Pacific. In this study, using monthly monitoring data from a water quality monitoring campaign during 2006–2012, the temporal variation and spatial transfer of six heavy metals (lead (Pb), copper (Cu), cadmium (Cd), zinc (Zn), arsenic (As), and mercury (Hg)) in the Pearl River were analyzed, and the heavy metal fluxes into the sea were calculated. During this period, the annual heavy metal loads discharged from the Pearl River into the South China Sea were 5.8 (Hg), 471.7 (Pb), 1524.6 (Cu), 3819.6 (Zn), 43.9 (Cd), and 621.9 (As) tons, respectively. The metal fluxes showed a seasonal variation with the maximum fluxes occurring from June to July. There is a close association between metal fluxes and runoff. The analysis of the heavy metal transfer from the upstream to the downstream revealed that the transfer from the upstream accounted for a major portion of the heavy metals in the Pearl River Delta. Therefore, earlier industry relocation efforts in the Pearl River watershed may have limited effect on the water quality improvement in surrounding areas. It is suggested that watershed-based pollution control measures focusing on wastewater discharge in both upstream and downstream areas should be developed and implemented in the future.