Aquatic ecological problems caused by pharmaceutical and personal care products (PPCPs) are increasingly becoming an issue of concern. In this study, the seasonal and spatial occurrence and environmental risk of 20 PPCPs were studied at 19 sampling points in the surface waters of the Lianjiang River basin (southern of China); its watershed is about 10,100 km2. Sample preparation was performed using solid-phase extraction, and determination was performed by using a high-performance liquid-phase tandem triple quaternary mass spectrometer. Nine PPCPs were detected with total concentrations of 19.5–940.53 and 6.07–186.04 ng L−1 during the wet (August 2021) and dry (April 2022) seasons, respectively. Four kinds of compounds—sulfamethoxazole (SMX), sulfamonomethoxine (SMM), caffeine (CAF), and florfenicol (FFC)—had a detection rate of more than 50% in both seasons. CAF, carbamazepine (CBZ), and FFC were higher in the wet season than in the dry season in the Lianjiang River possibly due to the higher usage of PPCPs and increased tourism during summer. SMX and SMM showed higher average concentrations in the dry season possibly due to lower biodegradation in the dry season and a slight dilution effect from rainfall. The concentrations of SMX, SMZ, SMM, and FFC were strongly correlated with NO3−, according to redundancy analysis and Spearman’s correlation analysis. The results of the risk quotient revealed that the ecological effect of CAF concentrations on green algae had low risk at all sampling points except R16.