Conventional water infrastructure designs for flood and low flows are usually based on the assumption of stationarity of extreme events. However, recent evidence suggests that the influences of climate variability and human activities have made the hypothesis of stationarity questionable. In this study, we used the generalized additive models for location, scale, and shape (GAMLSS) to construct a nonstationary model in which the parameters of the selected distributions were modelled as a function of climatic variables (i.e., climate indices and precipitation) and/or the reservoir index (RI). The nonstationary models were then used to analyse annual flood and low flow frequency at four hydrological stations in the upper reaches of the Huaihe River Basin, including Dapoling (DPL), Changtaiguan (CTG), Zhuganpu (ZGP), and Xixian (XX) stations. Annual floods were represented by the maximum daily streamflow in each year, and low flows were represented by the 95th quantile of the daily streamflow (Q95) in each year. The change point and trend analysis revealed that the flood series of the ZGP station and the low flow series of the DPL and XX stations exhibited significant downward and upward trends (p < 0.1)), respectively. The low flow series of the ZGP station showed a significant change point in 1980 (p < 0.1). GAMLSS modelling results showed that, in comparison with stationary models, nonstationary models that included precipitation and the Arctic Oscillation climate index as covariates for the gamma distribution location parameter provided a superior description of the flood series at the four stations. Nonstationary models that incorporated precipitation and/or RI as covariates for the Weibull distribution parameters fit the low flow series better than stationary models at all stations. Furthermore, we found that nonstationary models outperformed stationary models in terms of flood frequency analysis, covering all flood observation points and capturing the generally decreasing trend in flood series, as well as a decrease in the scatter of estimated flood value magnitudes. For the low flow frequency analysis, the comparison results showed that the nonstationary and stationary models performed identically for the DPL, CTG, and XX stations, where no significant change point was detected. However, for the ZGP station, where a significant change point was detected, the nonstationary models performed better than the stationary models and could accurately capture the changes in the magnitude of the estimated low flow values before and after the change point. Overall, the proposed nonstationary model can serve as a tool for nonstationary frequency analysis of flood and low flow series under the influence of climate variability and reservoir regulations, thus providing a reference for regional water infrastructure design.