Abstract: The research was conducted to investigate some physiological, biochemical and histopathological side effects induced by the administration of an overdose (900mg kg‾1 b.wt.) of the analgesic and antipyretic drug acetaminophen (APAP) on male albino rabbit. The work was also designed to compare the influence of L-methionine (37.7mg L-methionine kg‾1 b.wt. repeated every 4 for 12hr. up to a total dose of 142.8mg kg‾1 b.wt.) and/or phenethyl isothiocyanate (150μmol kg‾1 b.wt.) on the hazardous side effects of this drug. The results indicated that the administration of an overdose of APAP induced remarkable decreases in the number of red blood cells, haemoglobin contents (Hb), and haematocrit values (Ht). In addition to the elevations in the total bilirubin in the plasma. Also it induced leucopenia, granulocytopenia, and monocytopenia, which may be due to suppression in the organs necessary for their production (bone marrow and lymphatic organs) on the other hand, it induced lymphocytosis. It also caused liver dysfunction, as indicated by the elevation in the activities of alanine and aspartate aminotransferase (AST, ALT) and alkaline phosphatase (ALP) in plasma and the histopathological studies. It resulted in perturbations in the renal functions as indicated by marked rises in the concentrations of plasma creatinine, urea and uric acid. The histopathological examination indicated alterations in the cortex and S3 segment (pars recta). Overdose of the drug caused hypoglycaemia, increases in the concentration of total lipids and triglycerides and hypocholesterolaemia. The administration of L-methionine following an overdose of APAP succeeded in preventing all the disturbances in the tested hepatic and renal functions. It also increased the plasma and urinary levels of the detoxified metabolites of APAP (APAP-GSH, APAP-Cys, and APAP-merc) and decreased the plasma level of the parent APAP. The administration of PEITC following an overdose of drug succeeded in decreasing the haemato- and hepatotoxicities of APAP but it has serious effects on the renal function. The estimation of the drug and its metabolites indicated increases in the plasma and urinary concentration of APAP-gluc and APAP-sulphate as compared with APAP-treated group, while the concentration of the other studied metabolites decreased. The level of the parent APAP decreased in the plasma and administration of L-methionine together with PEITC succeeded completely in preventing the hepatotoxicity and in modulating the haematotoxicity but not the renal toxicity of APAP. The prominent outcome of this investigation that L-methionine is still superior to either PEITC alone or when administrated in combination with PEITC in modulating most of the toxic side effects of APAP.