Flood-frequency curves, critical for water infrastructure design, are typically developed based on a stationary climate assumption. However, climate changes are expected to violate this assumption. Here, we propose a new, climate-informed methodology for estimating flood-frequency curves under non-stationary future climate conditions. The methodology develops an asynchronous, semiparametric local-likelihood regression (ASLLR) model that relates moments of annual maximum flood to climate variables using the generalized linear model. We estimate the first two marginal moments (MM) – the mean and variance – of the underlying log-Pearson Type-3 distribution from the ASLLR with the monthly rainfall and temperature as predictors. The proposed methodology, ASLLR-MM, is applied to 40 U.S. Geological Survey streamgages covering 18 water resources regions across the conterminous United States. A correction based on the aridity index was applied on the estimated variance, after which the ASLLR-MM approach was evaluated with both historical (1951–2005) and projected (2006–2035, under RCP4.5 and RCP8.5) monthly precipitation and temperature from eight Global Circulation Models (GCMs) consisting of 39 ensemble members. The estimated flood-frequency quantiles resulting from the ASLLR-MM and GCM members compare well with the flood-frequency quantiles estimated using the historical period of observed climate and flood information for humid basins, whereas the uncertainty in model estimates is higher in arid basins. Considering additional atmospheric and land-surface conditions and a multi-level model structure that includes other basins in a region could further improve the model performance in arid basins.