Synthetic hexaploid wheat and their advanced derivatives (SYN-DERs) are promising sources for introducing novel genetic diversity to develop climate-resilient cultivars. In a series of field and laboratory experiments, we measured biochemical, physiological and agronomic traits in a diversity panel of SYN-DERs evaluated under well-watered (WW) and water-limited (WL) conditions. Analysis of variance revealed significant differences among genotypes, treatments and their interaction for all agronomic and physiological traits. Grain yield (GY) was reduced by 62.75% under WL, with a reduction of 38.10% in grains per spike (GS) and 19.42% in 1000-grain weight (TGW). In a Pearson’s coefficient correlation, GY was significantly correlated with GS, number of tillers per plant and TGW in both conditions. Path coefficient analysis showed that TGW and GS made the highest contribution to GY in WW and WL conditions, respectively. The traits examined in this experiment explained 59.6% and 63.01% of the variation in GY under WL and WW conditions, respectively; TGW, canopy temperature at spike and superoxide dismutase were major determinants of GY under WL conditions. The major flowering-time determinant gene Ppd-D1 was fixed in the diversity panel, with presence of the photoperiod-insensitive allele (Ppd-D1a) in 99% accessions. Wild-type alleles at Rht-B1 and Rht-D1, and presence of the rye translocation (1B.1R), favoured GY under WL conditions. Continuous variation for the important traits indicated the potential use of genome-wide association studies to identify favourable alleles for drought adaptation in the SYN-DERs. This study showed sufficient genetic variation in the SYN-DERs diversity panel to improve yields during droughts because of better adaptability than bread wheat.