In this study, long-term hydro-meteorological data from 1954 to 2018 from the Pearl River basin were used to investigate the impact of climate change and human activities on water discharge (WD) and sediment load (SL). The results revealed that the SL of the Pearl River exhibited a significant increasing trend at a rate of 1.38 × 104 t/yr from 1983 to 1988 and a significant decreasing trend at a rate of −2.24×104 t/yr from 1989 to 2018. WD exhibited a non-significant increasing trend of 0.3416×108 m3/yr during the entire period. The increasing trend of the SL can largely be attributed to exacerbated rocky desertification in the drainage basin, whereas the decreasing trend was mostly caused by an increase in the construction of dams and reservoirs. Mann-Kendall and double mass curve analyses revealed that a significant abrupt downward change occurred in the SL in 1998. However, the construction of dams and reservoirs in the Pearl River basin seems to have little influence on annual WD. The changes in annual WD were mainly caused by variations in precipitation. Although significant long-term changes in SL were detected, inter-annual fluctuations were found to be in good agreement with precipitation and WD data. Furthermore, El Niño/Southern Oscillation (ENSO) events are often associated with low precipitation, resulting in low WD and SL, indicating that changes in ENSO periodicity could affect the inter-annual periodic variations of WD and SL. Climate change and human activities contributed 63% and 37% to the increases in WD, respectively. The human-activities-induced decreases in SL were 1987 × 104 t/yr in the 1990s, 4143.17 × 104 t/yr in the 2000s, and 5259.83 × 104 t/yr in the 2010s. These results should serve as a reference for better resource management in the Pearl River basin.