In Serbia irrigation is not widely utilized to reduce water scarcity in crop production. Therefore, wheat yields largely depend on weather factors. Over the past two decades, there has been recorded a significant change in weather conditions in Serbia. Such change produces concerns about Serbia’s food security and exports since wheat is among the most important agricultural products. In this paper authors analyze and quantify the impact of weather factors on the achieved wheat yields, using a set of panel data on selected Serbian municipalities in fourteen years (2000–2013). The multidimensional regression was conducted as a sort of quasi-experiment, combining data on achieved yields in selected municipalities, with data on weather factors: temperature, precipitation, extraterrestrial radiation, and evapotranspiration. Utilizing the Hargreaves method of determining reference evapotranspiration, average daily water deficit was computed as a single representative indicator of weather conditions. Testing was conducted on four predefined sub-periods within the vegetation season of wheat, and the impact of average daily water deficit on wheat yields was estimated for each of these sub-periods. Results show a robust, statistically significant impact of change in average daily water deficit on decreased wheat yields. Growth of water deficit by 0.1 mm, in the period November 15th to April 1st results with 175 kg/ha lower yields, while in the period April 1st to May 15th results in 45 kg/ha lower yields. Impact shows to be conditional on the altitude, rapidly losing on intensity and significance above 100 m.