Crop yields are increasingly affected by climate change-induced weather extremes in Germany. However, there is still little knowledge of the specific crop-climate relations and respective heat and drought stress-induced yield losses. Therefore, we configure weather indices (WIs) that differ in the timing and intensity of heat and drought stress in wheat (Triticum aestivum L.). We construct these WIs using gridded weather and phenology time series data from 1995 to 2019 and aggregate them with Germany-wide municipality level on-farm wheat yield data. We statistically analyze the WI’s explanatory power and region-specific effect size for wheat yield using linear mixed models. We found the highest explanatory power during the stem elongation and booting phase under moderate drought stress and during the reproductive phase under moderate heat stress. Furthermore, we observed the highest average yield losses due to moderate and extreme heat stress during the reproductive phase. The highest heat and drought stress-induced yield losses were observed in Brandenburg, Saxony-Anhalt, and northern Bavaria, while similar heat and drought stresses cause much lower yield losses in other regions of Germany.