Quantifying the impacts of climate change and human activities on runoff changes is one of challenges in hydrology and water resources researches. In order to reveal the impacts of climate change and human activities on the interannual flow of a karst subterranean river system, this study chose a big karst subterranean river in south China, Nandong subterranean river (NSR) as a research area to analyse the interannual variations of precipitation, evapotranspiration and flow based on the data of flow, evapotranspiration and precipitation of NSR from 1972 to 2014. The results indicated that precipitation, evapotranspiration and flow of NSR during the study period showed a fluctuating decline trend, in which the overall declining rates of precipitation, evapotranspiration and flow were 3.14 mm/a, 7.49 mm/a and 0.014*10~8 m~3/a, respectively. Two inflection-point years in the variations of precipitation and flow, 2002 and 2008 were identified through the sequential clustering and Mann- Kendall test methods. The method of slope changing ratio of cumulative quantity was adopted in estimation of the contributions of climate change and human activities to the flow variations in NSR. Considering the influence of evapotranspiration in NSR, the results, with 1972-2002 as the base period, indicated less effect from human activities. The contribution rates of the climate changes to the flow changes were -86.68% in the T2 period (2003-2008), and 35.92% in the T3 period (2009- 2014), while the contribution rates of human activities were 186.68% in the T2 period and 64.08% in the T3 period. Obviously, human activities were the dominant factor causing the interannual flow change in NSR catchment. Direct water consumption of production and living and the changes of flow processes under the influences of land use/land cover changes exerted a main influence on the interannual flow changes. The results can give us a better understanding of the variation characteristics under the impacts of climate change and human activities and help to reasonably regulate karst water resources.