Consumption of fish and aquatic products is considered to be the main pathway of human exposure to methylmercury (MeHg). To assess human health risk through seafood consumption in a coastal area of Guangdong Province, South China, a total of 518 seafood samples (including fish, shrimp, crabs, and mollusks) were collected from 11 coastal cities for total mercury (THg) analysis. The THg concentrations varied significantly among different seafood groups and ranged from 0.11 to 317 ng/g (with a mean of 37.2 ng/g). The THg concentrations were relatively low compared with fish from Europe and North America, and no samples exceeded the national limit recommended by the Standardization Administration of China (0.5 ng/g wet wt). The ecological functional groups and cultured styles have significant effects on THg concentrations in the fish tissue. The median of probable daily intakes (PDIs) of MeHg via seafood consumption ranged from 42.6 to 71.4 ng/g for different age groups, with fish contributing the major portion (84%). The results indicated potential health risks associated with seafood consumption for the general population in the coastal area of Guangdong Province, South China.