Long-term hydro-climatic datasets and sophisticated change detection methods are essential for estimating hydro-climatic trends at regional and global scales. Here, we use the ensemble empirical mode decomposition method (EEMD) to investigate runoff oscillations at different time scales and its response to climatic fluctuations in the middle of the Yarlung Zangbo River Basin (MYZRB) over the period . In the study region, results revealed that the runoff presented an overall nonlinear and nonstationary decreasing-increasing alternative trend with weak quasi-three-year and unobvious quasi-five-year cycles at the inter-annual scale, while, significance was discovered with quasi-12-year and quasi-46-year cycles at the inter-decadal scale. Variance contribution rates of the hydrological components suggested that the inter-annual oscillations played an essential role in the runoff variations in the MYZRB. According to the reconstructed inter-decadal runoff series, the runoff may keep declining in future. For the response of runoff to climate change, overall, the runoff had a positive correlation with precipitation and a negative correlation with extreme temperature. But the runoff did not show obvious correlation with mean temperature. Furthermore, from a temporal scale point of view, the inter-annual runoff showed significant response to the inter-annual precipitation. The inter-decadal runoff strongly responded to the inter-annual extreme temperature. These findings will help us understand the hydro-climatic intrinsic mechanism in the MYZRB and develop better water resources management to account for climate change impact.