Methanol extract of Piper guineense seed was administered to Swiss albino rats to asses the effect on paracetamol induced toxicity. Thirty-six albino rats were divided into six groups of six animals per group. Four groups were administered in increasing doses of the extract 50, 100, 150, 200 mg/body weight where as the fifth group was administered 500kg/kg of paracetamol as the positive control, while the sixth group was used as normal control. The duration of the experiment was two weeks. This study revealed that the paracetamol increased the biochemical parameters. This was attenuated by the co-administration of Piper guineense extract by oral gavage (50, 100, 150, 200mg/kg b.w). The biochemical parameter studied showed consistent changes. The chronic administration of paracetamol 500 kg/b,w showed an elevation in ALT, AST, MDA, total protein, total bilirublin, total protein, globulin And a depletion of SOD(superoxide dismutase), catalase, ALP, Albumin and Albumin/ globulin GSH (reduced glutathione),levels. Administration of methanol extract of Piper guineense attenuated the levels ALT, AST, GSH( reduced glutathione), SOD(superoxide dismutase),total protein, total bilirublin, total protein, globulin levels. Piper guineense ameliorated MDA, catalase, urea, ALP, Albumin and Albumin/ globulin levels restoring it significantly. The histopathology results of the effect methanol extract of Piper guineense on paracetamol induced toxicity. It Concurs with the result of the biochemical parameters. From this study it can be concluded that methanol extract of Piper guineense possess some potent antioxidants which can ameliorate damage associated with chronic exposure to paracetamol exposure in rat models.