Melanoma is one of the most malignant skin cancers. Various treatment methods such as chemotherapy, radiotherapy, and particularly newer therapies like immunotherapy and targeted therapy have improved survival rates. However, high drug resistance rates, unaffordable treatment costs, and numerous side effects are the drawbacks of these methods. Recently, the role of β-adrenergic receptors in melanoma treatment has garnered attention. Some studies have reported that the use of propranolol, a β-adrenergic receptor antagonist, in vivo and in vitro, helps slow the growth of melanoma cells and limit metastasis. When combined with immunotherapies, propranolol improves the survival rates of patients. Our study evaluates the impact of isoproterenol (a β-adrenergic receptor agonist), norepinephrine (an α- and β-adrenergic receptor agonist), and propranolol on the A375 melanoma cell line. Our results show that isoproterenol and norepinephrine do not affect the proliferation of melanoma cells. Similar results were observed with propranolol at low concentrations (<100 µM). However, we found that propranolol at high concentrations (100, 200, 300, 400 µM) reduces cell proliferation and increases cell death. Furthermore, the combination of propranolol and norepinephrine at low concentrations (1 µM) inhibits the proliferation of melanoma cells more than propranolol alone. The mechanism could be explained by the synergistic effect of activating α-adrenergic receptors and inhibiting β-adrenergic receptors. This combination could open a new direction in melanoma treatment.