Worldwide periods of heat and drought are projected to be more frequent, longer, and occurring earlier, which could deleteriously affect the productivity of cool-season crops including wheat (Triticum spp.). The coexistence of heat and drought stresses affects plant biochemical and physiological processes including cell membrane function. The increased permeability and leakage of ions out of the cell has been used as a measure of cell membrane stability (CMS) and as a screen test for stress tolerance. The main objectives of this research were to: (1) screen a global spring wheat panel for CMS by exposing leaf tissue to heat treatment and osmotic pressure (PEG 600), (2) identify potential quantitative trait loci (QTL)/genes linked with CMS using genome-wide association mapping, and (3) estimate the relationship between the field performance and measured CMS. The results indicated highly significant differences among the 2111 spring wheat accessions regarding CMS. Moreover, several SNPs were found to be significantly linked with CMS. The annotation of the significant SNPs indicated that most of these SNPs are linked with important functional genes, which control solute transport through the cell membrane and other plant biochemical activities related to abiotic stress tolerance. Overall, this study demonstrated the use of genome-wide association mapping for the identification of potentially new genomic regions associated with CMS. Tolerant genotypes identified in this study proved to be more productive under preliminary field stress conditions. Thus, the identified membrane-stable accessions could be used as parental genotypes in breeding programs for heat or drought stress tolerance.