As heatwaves and drought episodes occur concurrently in many drylands, it is important to study them together to facilitate climate resilience breeding. Here, we examined the combined effect of heat and drought stress in wheat through a series of experiments including field trials in Sudan and greenhouse screening and growth chamber elucidation of tolerance mechanism in Japan. Novel genomic regions controlling agronomic and physiological traits including carbon isotope ratio (δ13C) and grain yield stability were identified. Two alternative water conservation mechanisms were identified as high and low fraction of transpirable soil water threshold (FTSWTh). The high FTSWTh mechanism resulted in effective water use under dry-down conditions and may be better suited for erratic rainfall conditions. The low FTSWTh mechanism promotes water saving and may be better suited for prolonged drought conditions. Further analysis revealed differences in metabolite profiles between the high and low FTSWTh lines, suggesting their role in promoting water-use efficiency in wheat under combined heat- and drought-stressed conditions.