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Acute myeloid leukemia (AML) is one of the cancers that grow most aggressively. The challenges in AML management are huge, despite many treatment options. Mutations in FLT3 tyrosine kinase receptors make the currently available therapies less responsive. Therefore, there is a need to find new lead molecules that can specifically target mutated FLT3 to block growth factor signaling and inhibit AML cell proliferation. Our previous studies on FLT3-mutated AML cells demonstrated that β-elemene and compound <b>5a</b> showed strong inhibition of proliferation by blocking the mutated FLT3 receptor and altering the key apoptotic genes responsible for apoptosis. Furthermore, we hypothesized that both β-elemene and compound <b>5a</b> could be therapeutically effective. Therefore, combining these drugs against mutated FLT3 cells could be promising. In this context, dose–matrix combination-based cellular inhibition analyses, cell morphology studies and profiling of 43 different apoptotic protein targets via combinatorial treatment were performed. Our studies provide strong evidence for the hypothesis that β-elemene and compound <b>5a</b> combination considerably increased the therapeutic potential of both compounds by enhancing the activation of several key targets implicated in AML cell death.