Chloroquine was once thought to be a promising treatment for COVID-19 but it quickly failed due to its inefficiency and association with increased mortality. Further, comorbidities such as hypertension may have contributed this failure. The safety and toxicity of chloroquine at doses required for treating SARS-CoV-2 infection in hypertensive patients remain unknown. Herein, to investigate these effects, we performed a safety evaluation of chloroquine at the approved dose (63 mg/kg) and at a high dose (126 mg/kg) in hypertensive rats. We found that chloroquine increased the mortality of hypertensive rats to 18.2% and 100%, respectively, after 7 days. During the chloroquine exposure period, the bodyweight, feed, and water consumption of hypertensive rats were decreased significantly. In addition, we show that chloroquine induces prolongation of QTc interval, elevation of LDH and CK, and histopathological damage of the myocardium in hypertensive rats. Ocular toxicity was observed in hypertensive rats in the form of hemorrhage in the eyes and retinal damage. Furthermore, we also observed intestinal toxicity in hypertensive rats, which presented as thinning intestinal walls with hemorrhagic contents, and histopathological changes of the jejunum. Hepatotoxicity was also evidenced by elevated ALT, and vacuolization of hepatocytes was also observed. Nephrotoxicity was observed only in high dose chloroquine-treated hypertensive rats, presenting as alterations of urinalysis and renal function. Immune alterations were also found in high-dose chloroquine-treated hypertensive rats with elevation of serum IL-10, IL-1β and GRO, and moderate damage to the spleen. In summary, this study partially explains the reason for the failure of chloroquine as a COVID-19 therapy, and underlines the importance of safety evaluation and medical supervision of chloroquine to avoid patient harm, especially to those with hypertension.Keywords: COVID-19; antiviral drug; chloroquine; hypertension; safety evaluation; toxicology.