In Mediterranean environments, water deficiency and heat during reproduction severely limit cereal crop production. Our research investigated the effects of single and combined pre-anthesis water-deficit stress and post-anthesis heat stress in ten Australian durum genotypes, providing a systematic evaluation of stress response at the molecular, physiological, grain quality and yield level. We studied leaf physiological traits at different reproductive stages, evaluated the grain yield and quality, and the associations among them. We profiled the expression dynamics of two durum microRNAs and their protein-coding targets (auxin response factors and heat shock proteins) involved in stress adaptation. Chlorophyll content, stomatal conductance and leaf relative water content were mostly reduced under stress, however, subject to the time-point and genotype. The influence of stress on grain traits (e.g., protein content) also varied considerably among the genotypes. Significant positive correlations between the physiological traits and the yield components could be used to develop screening strategies for stress improvement in breeding. Different expression patterns of stress-responsive microRNAs and their targets in the most stress-tolerant and most stress-sensitive genotype provided some insight into the complex defense molecular networks in durum. Overall, genotypic performance observed indicates that different stress-coping strategies are deployed by varieties under various stresses.