This study presented a framework to select a suitable time-varying moment (TVM) model for non-stationary flood frequency analysis based on the daily flow observation data at Chiang Saen Station, Mekong River from 1960 to 2019, the impacts of cascade reservoir construction on the flood frequency were further explored. The results showed that the annual maximum daily flow series of Chiang Saen Station exhibited a significant decreasing trend (p<0.01); the combination of generalized logistic distribution (GLO) and the AL linear trend model could obtain the optimal fitting; compared with the conventional frequency analysis, the design flow of 100 a obtained by the TVM model decreased with time, but the return period showed an upward trend. The upstream cascade reservoirs had an obvious regulation effect on the peak flow of 100 a flood at Chiang Saen Station especially after the operation of Nuozhadu Reservoir, which had a positive effect on the downstream flood control.