Based on the Lancang River Basin (LRB) hydro–meteorological data from 1961 to 2015, this study uses the Mann–Kendall trend test and mutation test to analyze the trend of hydro–meteorological variables, as well as which year the runoff series changes, respectively. We applied the Choudhury–Yang equation to calculate the climate and catchment landscape elasticity of runoff. Then we quantified the impact of climate change and human activities on runoff change. The results show that: (1) the mean annual precipitation (P) in LRB showed an insignificant decline, the annual potential evapotranspiration (E₀) showed a significant increase, and the runoff depth (R) showed a significant decrease; (2) the abrupt change of the R occurred in 2005. Both the climate and catchment landscape elasticity of runoff increased, which means that the hydrological process of LRB became more sensitive to climate changes and human activities; (3) compared with the base period (1961–2004), the reduction of P was the leading cause of runoff reduction, with a contribution of 45.64%. The contribution of E₀ and human activities to runoff changes are 13.91% and 40.45%, respectively.