Heat stress along with low water availability at reproductive stage (terminal growth phase of wheat crop) is major contributing factor towards less wheat production in tropics and sub-tropics. Flag leaf plays a pivotal role in assimilate partitioning and stress tolerance of wheat during terminal growth phase. However, limited is known about biochemical response of flag leaf to combined and individual heat and drought stress during terminal growth phase. Therefore, current study investigated combined and individual effect of terminal drought and heat stress on water relations, photosynthetic pigments, osmolytes accumulation and antioxidants defense mechanism in flag leaf of bread wheat. Experimental treatments comprised of control, terminal drought stress alone (50% field capacity during reproductive phase), terminal heat stress alone (wheat grown inside plastic tunnel during reproductive phase) and terminal drought stress + terminal heat stress. Individual and combined imposition of drought and heat stresses significantly (p≤0.05) altered water relations, osmolyte contents, soluble proteins and sugars along with activated antioxidant defensive system in terms of superoxide dismutase (SOD), peroxidase (POD) and ascorbate peroxidase (APX). Turgor potential, POD and APX activities were lowest under individual heat stress; however, these were improved when drought stress was combined with heat stress. It is concluded that combined effect of drought and heat stress was more detrimental than individual stresses. The interactive effect of both stresses was hypo-additive in nature, but for some traits (like turgor potential and APX) effect of one stress neutralized the other. To best of our knowledge, this is the first report on physiological and biochemical response of flag leaf of wheat to combine heat and drought stress. These results will help future studies dealing with improved stress tolerance in wheat. However, detailed studies are needed to fully understand the genetic mechanisms behind these physiological and biochemical changes in flag leaf in response to combined heat and drought stress.