The crop simulation model Decision Support System for Agrotechnology Transfer (DSSAT) was applied over the Mekong River Delta (MRD), Southern Vietnam, to assess future (2020–2050) impacts of climate change on rice production. The DSSAT model was driven using observed station data and projected climate data derived through the dynamical downscaling of three global climate models (GCMs) using the Weather Research and Forecasting (WRF) model. The WRF model was simulated at a spatial resolution of 30 km over the study region, and the large-scale driving fields for future climates were taken from the Coupled Model Inter-Comparison Project Phase 3 (CMIP3) global models ECHAM5, CCSM3, and MIROC5 under the A2 emission scenario. Rice growth during two main seasons, namely, the winter-spring (winter) and summer-autumn (summer), were selected to quantify impacts under both irrigated and rain-fed rice cultivation. The results from this climate-crop study suggest that under rainfed conditions, winter rice yield was likely to experience nearly 24% reduction while summer rice yield was projected to decrease by about 49%. Without irrigation, the annual rice yield was projected to decrease by about 36.5%, and under irrigated conditions, climate change is likely to reduce annual irrigated rice yields by about 1.78%. Winter rice yield was likely to decrease by 4.7% while summer rice yield was projected to marginally increase by about 0.68%. Increasing temperatures and seasonal variations of precipitation are likely to significantly reduce rice yields under rain-fed condition. In addition, (1) a decrease (increase) in the number of rainy days during the dry (wet) season and (2) positive effects of elevated CO2 for rain-fed rice growth under each of the three WRF model realizations would markedly influence rice yields. With Vietnam being one of the largest exporters of rice, these findings have serious implications for the local agricultural sector. This also serves an early warning for the policymakers and stakeholders for effective planning of not only crop production but also water resource management. The findings call for prudent diversification strategy planning by those countries which import rice.