<p>In a circadian cycle, the pineal gland produces and releases melatonin (MEL) into the bloodstream. By activating distinct melatonin receptors, MEL has been shown to variably change vascular endothelial dysfunction (VED) to various vascular beds. This study investigates the interaction of melatonin (MEL) and potassium ion (K⁺) on angiotensin 1–7 (Ang 1–7) vasorelaxant in streptozotocin (STZ)–induced diabetes mellitus (DM) and non-diabetes mellitus (non-DM) male albino rat aortic rings. The isometric tension of isolated aortic rings was assessed by generating a dose–response curve (DRC) for Ang 1–7 using a PowerLab data acquisition system. Accordingly, three experimental sets were carried out. In the first set the aortic rings were exposed MEL and MEL agonist ramelteon (RAM) and MEL antagonist luzindole (LUZ). In the second set, the aortic rings were exposed to various non-selective calcium activated potassium channel (K_Ca) blockers, including tetraethylammonium (TEA), a small and large-conductance calcium-activated K⁺ [(SK_Ca) and (BK_Ca)] channels blocker charybdotoxin (ChTx) and intermediate calcium-activated K⁺ channel (IK_Ca) blocker clotrimazole (CLT). In the third set, the aortic rings were exposed to various selective K⁺ channels blockers, including the selective blocker of K_ATP channel, glibenclamide (Glib), 4-aminopyridine (4-AP), a selective blocker of K_v channels and BaCl₂, delayed inward rectifier K⁺ channels (K_ir) blocker. The results highlight the significant role of MEL in modulating vascular reactivity, particularly in the DM aorta. By enhancing the vasorelaxant effects of Ang 1–7 through mechanisms involving its receptors and antioxidant activities, MEL demonstrates its potential to counteract oxidative stress and VED associated with diabetes. These findings advance the understanding of vascular reactivity in diabetes and suggest MEL as a promising therapeutic agent for improving vascular health in diabetic conditions.</p>