Background: Paracetamol (acetaminophen) is one of the over-the-counter analgesic antipyretic drugs. It is associated with hepatotoxicity and nephrotoxicity in overdose. Spirulina, and Butylated hydroxytoluene are valuable antioxidants. Cilostazol is a phosphodiesterase type 3 inhibitor with protective effects in some hepatic and renal injury models. Aim of the work: This study aims to evaluate the ameliorative effect of spirulina, BHT, and cilostazol against paracetamol-induced hepatotoxicity and nephrotoxicity. Material and Methods: fifty-four- adult male Wistar rats were classified into 9 equal groups: I (Control group), II (Paracetamol group), III (Spirulina group), IV (BHT group), V (Cilostazol group), VI (Paracetamol + Spirulina preventive group), VII (Paracetamol + BHT preventive group), VIII (Paracetamol + Spirulina+ BHT preventive group) and IX (Paracetamol + Cilostazol treatment group). Blood samples were collected at the end of the study and rats were then sacrificed and livers and kidneys were handled for biochemical, histopathological, and immunohistochemical studies. Results: Paracetamol overdose persuaded a significant elevation in serum liver enzymes (AST, ALT and ALP), urea, and creatinine levels. Also, it induced a significant elevation in serum MDA with a substantial decrease of hepatic GST, SOD in the liver, and catalase in the kidney. It also increased the expression of MAPK, JNK, IL8, NF-κB1, BAX and immunohistochemical P53. The administration of spirulina, BHT, and cilostazol with paracetamol significantly improves these previous parameters, implying that hepatic and renal tissues were sheltered from paracetamol’s hazardous effects. Conclusion: Spirulina, BHT and Cilostazol administration ameliorated Paracetamol hepatotoxicity and nephrotoxicity through antioxidant, anti-inflammatory, and anti-apoptotic impacts.