Pharmaceuticals are of increasing environmental concern due to their potential threat to aquatic ecosystems. Intensive human activities are a major factor influencing the level of pharmaceutical pollution in aquatic ecosystems. In this study, we investigated the occurrence, ecological risks of 31 pharmaceuticals and the possible influence of human activities on pharmaceutical distribution in two watersheds in the Yangtze River Delta, Eastern China. The target compounds were grouped into six categories: three non-steroidal anti-inflammatory drugs, ten antibiotics, six cardiovascular drugs, five hormones, six psychotropic drugs, and one antiparasitic. All target pharmaceuticals were detected in the surface water samples, with dexamethasone (100% of samples), tetracycline (100% of samples), and cefradine (100% of samples) being the dominant compounds (maximum concentrations of 686, 128, and 2280 ng/L, respectively). The total pharmaceutical concentrations were significantly higher in the urban watershed (711–2790 ng/L, mean = 1150 ng/L) than in the peri-urban watershed (467–1525 ng/L, mean = 863 ng/L) (p < 0.05). Distinct variation in the total pharmaceutical concentration also occurred between the dry season (507–2790 ng/L, mean = 1100 ng/L) and the wet season (467–1525 ng/L, mean = 943 ng/L). Ecological risk assessment showed that in the two watersheds, benzylpenicillin potassium, tetracycline hydrochloride, chlormadinone, ampicillin, cefotaxime acid, atorvastatin, sertraline hydrochloride, and oxazepam posed a medium potential risk (0.1 < risk quotient < 1), while norethisterone posed a high potential risk (risk quotient > 1). Redundancy analysis revealed that the concentrations of pharmaceuticals in various categories were positively correlated with land-use type (urban and agricultural land-use percentages), population density, and distance from town in both watersheds. Urban and agricultural activities were likely the main factors influencing the concentrations and composition of pharmaceuticals in these aquatic environments. Positive correlations were also found between total pharmaceutical concentrations and population density in both watersheds, suggesting a significant contribution of human disturbance to pharmaceutical pollution. The results provide useful information for pharmaceutical pollution control, ecological risk assessment, and sustainable water management at the watershed scale.