Climate change and intensive anthropogenic activities have severely challenged the water quality of China’s Pearl River Estuary (PRE). Further investigations into long-term water quality variation and associated driving mechanisms are therefore necessary to support the sustainable development of the PRE’s Greater Bay Area (GBA). This study used remote sensing retrieval to address long-term spatiotemporal chlorophyll-a (Chl-a) variation characteristics in the PRE and the relationship between Chl-a concentrations and socioeconomic/environmental indicators. Three decades of Landsat satellite images and measured data were collected, and a two-band global algorithm was used to retrieve Chl-a concentration data. Results reveal significant spatiotemporal variability in Chl-a concentrations. The space-averaged Chl-a concentration exhibited a slight downward trend during the past three decades, and the multi-year mean value was 5.20 mg/L. Changes to environmental protection policies in recent years have improved overall PRE water quality. The western section of the PRE had the highest Chl-a concentration (i.e., 5.92 mg/L average) while the eastern section had the lowest (i.e., 3.98 mg/L average). This discrepancy was likely caused by the western section’s more intensive industrial activities, resulting in a higher overall wastewater discharge volume. Affected by climatic conditions, winter Chl-a concentrations were evenly distributed while summer concentrations were significantly higher. Additionally, Chl-a concentrations significantly and positively correlated with total phosphorus (TP), total nitrogen (TN), ammonia nitrogen (NH₃-N), and the biotic oxygen demand (BOD₅). Chl-a concentrations also correlated with external factors (i.e., climate and anthropogenic activities). Among these factors, industrial wastewater discharge and the proportion of primary industries in coastal cities significantly and positively correlated with water quality. This study is intended to help direct water quality improvement management and urban sustainable development in the GBA.