In situ observations over 42 years were used to explore the long-term changes to low-oxygen conditions in the Pearl River estuary. Apparent expansion of the low-oxygen conditions in summer was identified, primarily due to the combined effects of increased anthropogenic inputs and decreased sediment load. Large areas of severe low-oxygen events were also observed in early autumn and were formed by distinct mechanisms. The estuary seems to be growing into a seasonal, estuary-wide hypoxic zone.