Bread wheat (Triticum aestivum L.) is a popular cereal crop worldwide, but its future use is threatened by its limited genetic diversity because of the evolutionary bottleneck limiting its ability to combat abiotic and biotic stresses. However, synthetic hexaploid wheat (SHW) is known for its genetic diversity resulting from of the artificial crossing used to transfer elite genes from donors. SHW is therefore a potential source for genetic variations to combat stress. We studied two SHW lines from CYMMIT (cSHW339464 and cSHW339465) and a Korean bread wheat (cv. KeumKang) to determine their ability to tolerate heat stress and leaf rust infection. Our results showed that cSHW339464 could tolerate heat stress because of its maintained-green phenotype, high accumulation of anthocyanin, antioxidant activity (DPPH), proline content, and the response of heat-shock proteins after being challenged by heat stress. On the other hand, cSHW339465 is resistant to leaf rust and can inhibit the growth of pathogens on the leaf surface, owing to the induction of genes encoding β-1,3-glucanase and peroxidase and subsequent enzyme activities. In conclusion, these two SHW lines could prove good candidates contributing to the improvement of current wheat resources.