In a changing climate, extreme weather events such as heatwaves will be more frequent and could affect grain weight and the quality of crops such as wheat, one of the most significant crops in terms of global food security. In this work, we characterized the response of Triticum turgidum L. spp. durum wheat to short-term heat stress (HS) treatment at transcriptomic and physiological levels during early grain filling in glasshouse experiments. We found a significant reduction in grain weight (23.9%) and grain dimensions from HS treatment. Grain quality was also affected, showing a decrease in starch content (20.8%), in addition to increments in grain protein levels (14.6%), with respect to the control condition. Moreover, RNA-seq analysis of durum wheat grains allowed us to identify 1590 differentially expressed genes related to photosynthesis, response to heat, and carbohydrate metabolic process. A gene regulatory network analysis of HS-responsive genes uncovered novel transcription factors (TFs) controlling the expression of genes involved in abiotic stress response and grain quality, such as a member of the DOF family predicted to regulate glycogen and starch biosynthetic processes in response to HS in grains. In summary, our results provide new insights into the extensive transcriptome reprogramming that occurs during short-term HS in durum wheat grains.