The impacts of various climatic conditions, such as temperature and rainfall variabilities, are very critical and sensitive to rain-fed crop production, particularly over the water stress arid and semi-arid regions of Ethiopia. This study was designed to evaluate the potential impact of climate variability and change on sorghum grain yield in the Babile district of eastern Ethiopia. The study was conducted based on observed and model-based simulated projected rainfall and temperature obtained from the Ethiopian Meteorological Institute and General Circulation Models (GCM) used by the Intergovernmental Panel on Climate Change (IPCC) of the Fifth Assessment Report CMIP5) and Agricultural Model Inter-comparison and Improvement Project (AgMIP). Three GCM models, namely GFDLESM2M, CanESM2, and HadGEM2-ES under RCP4.5, were considered to generate future climate projections for the near-term 21st century. Various univariate and multivariate statistical techniques were employed to compute and identify whether the impacts of climate variability and change on rain-fed sorghum crop performance were reasonably viable over the districts where grain yield is highly stable and productive under normal climate conditions. Our findings revealed that more stable and better rainfall performance from May to September, the season when sorghum crops are normally planted in the Babile district, was positively correlated, while the maximum and minimum temperatures of the season were negatively correlated with sorghum grain yield. A significant association has been detected between sorghum grain yield and its growing period rainfall, number of rainy days, and maximum and minimum temperature with multi-regression analysis. Thus, the variability of rainfall in August, June temperature, and the number of rainy days in September significantly impacted sorghum crop productivity. As a result, the multi-regression model adjusted R-squared indicated that 77% variance in annual sorghum yield performance was explained by rainfall and temperature conditions that prevailed during the crop growing period. During the past period, there was a significant increase in sorghum yields, which are projected to decline during the near term of the 21st century in the future. This revealed that declining and disturbed rainfall performance and increases in temperature are likely to reduce overall sorghum grain yield in the Babile district. We recommend that there is a need to enhance awareness for smallholder farmers on the adverse impact of climate variability and change on sorghum grain yield. In view of this, the farmers need to be geared toward employing climate-smart agriculture as a possible adaptation measure to reduce the negative impacts of climate variability and change on rain-fed crop production practices in the Babile district and other arid and semi-arid parts of eastern Ethiopia.