A method based on Sr, Nd and Pb multi-isotopic systems indicates that the different rock types (carbonate rock, basalt and black rock series) and sulfide deposits exposed in the Pearl River Basin show markedly different Sr, Nd and Pb isotopic characteristics. By establishing the mass balance equations of heavy metal content and isotope ratios, we use the inverse method to obtain the contribution that natural weathering of carbonate rocks, basalts and black rock series as well as the mining of sulfide deposits have on heavy metal content in riverbed sediments in the Pearl River Basin. Even though carbonate rocks constitute more than 60% of the exposed area in the upper reaches of the Pearl River Basin, this lithology only contributes 9% of the heavy metal content in sediments due to the relatively low content of heavy metals found in this rock type. Basalt weathering on average contributes 64% of the Cr content and 42% of the Ni content found in the sediments, while 53% of the Cd content is derived from the weathering of the black rock series. The negative impact mining has on this environment cannot be ignored as it is the most important source of As (71%) and Pb (60%) in all samples. This is especially the case in the Diaojiang River Basin, where sulfide mining activities still contribute more than 90% of the content of Zn, Pb, Cd and As within the sediments even though many mining sites have been closed since 2000.