We applied the newly developed WRF-Hydro model to investigate the hydroclimatic trend encompassing the three basins in Southwest Louisiana as well as their connection with large-scale atmospheric drivers. Using the North American Land Data Assimilation System Phase 2 (NLDAS-2), we performed a multi-decadal model hindcast covering the period of 1979–2014. After validating the model’s performance against available observations, trend and wavelet analysis were applied on the time series of hydroclimatic variables from NLDAS-2 (temperature and precipitation) and model results (evapotranspiration, soil moisture, water surplus, and streamflow). Trend analysis of model-simulated monthly and annual time series indicates that the regional climate is warming and drying over the past decades, specifically during spring and summer (growing season). Wavelet analysis reveals that, since the late 1990s, the anomaly of evapotranspiration, soil moisture, and streamflow exhibits high coherency with that of precipitation. Pettitt’s test detects a possible change-point around the year 2004, after which the monthly precipitation decreased from 140 to 120 mm, evapotranspiration slightly increased from 80 to 83 mm, and water surplus decreased from 60 to 38 mm. Changes in regional climate conditions are closely correlated with large-scale climate dynamics such as the Atlantic Multidecadal Oscillation (AMO) and El Niño Southern Oscillation (ENSO).