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This study investigates the impact of histamine H₂ receptor activation on glucocorticoid receptor (GR)-mediated transcriptional activity, as well as its effects on leukemic cell proliferation and chemotherapy resistance. We demonstrate that activation of the histamine H₂ receptor by its specific agonist, amthamine, enhances GR transcriptional activity induced by dexamethasone in both artificial promoter-driven luciferase reporter assays and endogenous GR-responsive genes. Mechanistically, histamine H₂ receptor signaling exerts a dual regulatory effect: an inhibitory influence mediated by cAMP and a stimulatory effect through inhibition of the PI3K-AKT-mTOR-S6K pathway and activation of the ERK pathway. Furthermore, while dexamethasone reduces leukemic cell proliferation at high doses, it increases it at lower concentrations, an effect that is abrogated by amthamine. Moreover, the combination of the glucocorticoid and the H₂ agonist reestablishes leukemic cell sensitivity to cytarabine, thereby restoring its cytotoxicity. Together, these findings offer insight into the molecular mechanisms and therapeutic potential of the interplay between histamine H₂ ligands and GR agonists, and may help guide dosage optimization and mitigate the well-known side effects of glucocorticoid therapy, with potential clinical implications for the treatment of acute myeloid leukemia.