Synthetic hexaploid wheat (SHW; 2n = 6x = 42, AABBDD, Triticum aestivum L.) is produced from an interspecific cross between durum wheat (2n = 4x = 28, AABB, T. turgidum L.) and goat grass (2n = 2x = 14, DD, Aegilops tauschii Coss.) and is reported to have significant novel alleles-controlling biotic and abiotic stresses resistance. A genome-wide association study (GWAS) was conducted to unravel these loci [marker?trait associations (MTAs)] using 35,648 genotyping-by-sequencing-derived single nucleotide polymorphisms in 123 SHWs. We identified 90 novel MTAs (45, 11, and 34 on the A, B, and D genomes, respectively) and haplotype blocks associated with grain yield and yield-related traits including root traits under drought stress. The phenotypic variance explained by the MTAs ranged from 1.1% to 32.3%. Most of the MTAs (120 out of 194) identified were found in genes, and of these 45 MTAs were in genes annotated as having a potential role in drought stress. This result provides further evidence for the reliability of MTAs identified. The large number of MTAs (53) identified especially on the D-genome demonstrate the potential of SHWs for elucidating the genetic architecture of complex traits and provide an opportunity for further improvement of wheat under rapidly changing climatic conditions.