The existing methods of measuring combined toxicity of heavy metal mixtures in environment do not fully consider three major factors (i.e., number of heavy metal species, aquatic biota, all investigated sites as an entity). Herein, a new method named joint probabilistic risk (JPR) method is proposed for evaluating the combined toxicity of heavy metal mixtures to aquatic biota. In this new method, the above three factors are fully taken into account. In order to evaluate the feasibility of the new method, the Pearl River Estuary (PRE) is selected as a case study. Concentrations of heavy metals (Cd, Pb, Cr, Ni, Cu, and Zn) in surface sediments of PRE are investigated and toxic equivalent factors (TEFs) of these heavy metals are calculated. Based on TEFs, sedimental concentrations of heavy metals of PRE are converted to Cd toxic equivalent concentration (Cdeq), while the Cd toxicity data (Cdto) are extracted from the literature. The probability density curves for Cdeq and Cdto are constructed and the overlap area is quantified as 0.2497. This indicates that the surface sediments of PRE have a 24.97% probability of toxic effect towards aquatic biota. Finally, this new method is validated by two indirect methods of mERMq and mPELq.