ETHNOPHARMACOLOGICAL RELEVANCE: Celosia argentea L. (Amaranthaceae), popularly known as "crista de galo", is used in folk medicine due to its diuretic and hypotensive effects. However, there are no reports in the literature regarding its pharmacological effects on the cardiovascular system as well as no data proving the safety of this species. AIM: To perform a detailed ethnopharmacological investigation of the ethanol soluble fraction from C. argentea (ESCA) using male and female Wistar rats. MATERIAL AND METHODS: Firstly, a morpho-anatomical characterization was performed to determine the quality control parameters for the identification of the species under investigation. Then, the ethanol extract was obtained and chemically characterized by LC-DAD-MS. Furthermore, an oral acute toxicity study was performed in female Wistar rats. Finally, the possible diuretic and hypotensive effects of three different doses of ESCA (30, 100 and 300 mg/kg) were evaluated in male Wistar rats. Besides, the vasodilatory response of ESCA in mesenteric vascular beds (MVBs) and its involvement with nitric oxide/cGMP and prostaglandin/cAMP pathways as well as potassium channels were evaluated. RESULTS: The main secondary metabolites present in ESCA were phenolic compounds, megastigmanes and triterpenoid saponins. ESCA caused no toxic effects in female rats nor increased urinary excretion in male rats after acute administration. However, ESCA significantly increased the renal elimination of potassium and chloride, especially at the end of 24 h after administration. Intermediary dose (100 mg/kg) of ESCA was able to promote significant acute hypotension and bradycardia. Moreover, its cardiovascular effects appear to be involved with the voltage-dependent K+ channels activation in MVBs. CONCLUSION: This study has brought new scientific evidence of preclinical efficacy of C. argentea as a hypotensive agent in normotensive rats. Apparently, these effects are involved with the activation of the voltage-sensitive K+ channels contributing to the reduction of peripheral vascular resistance and cardiac output.