Background:Unsweetened natural cocoa powder (UNCP), prepared after removal of the cocoa butter, is a common beverage in Ghana. It possesses antimalarial prophylactic property and has a beneficial effect on blood components.Aim:The aim of this study was to determine whether regular dietary supplement of UNCP mitigates high-dose (HD) artemether-lumefantrine (A-L)-induced hematological disorders and to determine the effect on nitric oxide (NO) levels.Materials and Methods:Adult male guinea pigs (300 g - 350 g) were randomly divided into 5 groups of 6 guinea pigs each. Among the 5 groups, 3 groups were treated with UNCP (300, 900, and 1500 mg/kg body weight) for 14 days. A-L (75 mg/kg) was administered from the 12th to 14th day. One of the remaining 2 groups received distilled water only, i.e., vehicle control group (VCG) while the other received 75 mg/kg A-L only, i.e., negative control group (NCG). Blood samples from all groups were obtained by cardiac puncture (day 15) followed by hematological and NO analysis.Results:A-L reduced white blood cells (WBC) by 31.87%, lymphocyte count by 45.99%, hemoglobin by 11.72%, hematocrit by 18.56%, and platelet count by 33.08% in the NCG. Administration of various doses of UNCP increased WBC and lymphocyte count (P > 0.05) compared to the NCG. UNCP and A-L combination caused an increase in NO levels when compared to the VCG.Conclusion:Regular consumption of UNCP by guinea pigs increases plasma NO and restores some hematological disorders induced by a 3-day HD A-L administration.