This study investigated the occurrence, distribution, and potential sources of 34 pharmaceuticals and personal care products (PPCPs) in water, sediments, aquatic organisms (fish and shellfish), and fish feeds from the mariculture areas of the Pearl River Delta (PRD). The health risk presented by this class of compounds was also assessed in relation to their intake via seafood consumption. Of the 34 PPCPs, a total of 9, 21, 14, and 28 PPCPs were detected in water, sediments, fish feeds, and aquatic organisms, respectively. Trimethoprim, norfloxacin, ofloxacin, and spectinomycin were detected in all matrices. The levels of PPCPs in water and sediment samples were relatively low. Spectinomycin, paracetamol, ciprofloxacin, norfloxacin, and ibuprofen were the most frequently detected PPCPs in feeds. Ibuprofen and ketoprofen were widely detected in aquatic organisms, with average concentrations of 562 and 267 ng/g wet weight, respectively. The residual levels of PPCPs in shellfish such as ME (mussel, Mytilus edulis) and OS (oyster, Ostrea gigas) were significantly higher (p < 0.05) than those in other species including CA (topmouth culter, Culter alburnus) and EO (orbfish, Ephippus orbis). Correlation analysis indicated that the medicated feeds were a potential source of PPCPs in the mariculture areas of the PRD, but other anthropogenic sources should not be ignored. Based on maximum residue limits and acceptable daily intake, the health risks presented to humans via seafood consumption are negligible. However, as multiple antibiotics were frequently detected in the mariculture environment, aquatic organisms, and feeds, the induction and dissemination of antimicrobial resistance associated with antibiotic usage in aquaculture would be of great concern. It is necessary to establish a centralized management system and control the use of veterinary drugs in mariculture to protect the aquaculture environment and ensure the safety of seafood.