Estuary connects the inland freshwater and open seawater, which may become a sink for pollutants from land-derived outflows, especially for persistent organic pollutants (e.g., polycyclic aromatic hydrocarbons, PAHs). Due to complex fluctuation in estuary, it's difficult to achieve a comprehensive assessment of the pollution characteristics by grabbed environmental samples. Oysters serve as efficient biomonitors of pollution status in highly dynamic and anthropogenically impacted estuaries, like the Pearl River Estuary (PRE), South China. Here, we investigated the annual, seasonal, and spatial variations of PAHs in the soft tissues of oysters from the PRE over the last six years (2015–2020) and quantitatively analyzed the influence of environmental factors on PAH occurrence in the oysters. The concentrations of Σ15PAH in oysters ranged from 74 to 1164 (337 ± 218) ng/g dry wt., with a peak occurrence in 2017. Highly seasonal and geographical variations in PAH pollution were documented in the PRE, with higher concentrations in oysters during the wet season than dry season, and in the eastern coast than western coast. Furthermore, geographical variation in PAH levels in the oysters was enhanced during the wet season, indicating a possible contribution of heavy rainfall flushing from the Pearl River. In addition to precipitation, water temperature and salinity also significantly influenced PAH levels in the oysters from the PRE by changing the bioavailability and biokinetics. Long-term biomonitoring using oysters in the current study reflected the pollution status and variation trends of PAHs in the highly dynamic PRE.