In this era, global attention has been directed towards the use of natural antioxidants to protect against drug-related effects. The vital role of natural antioxidant agents is the protection against free radicals. This study was conducted to evaluate the impacts of sugarcane peel extract on splenic complications induced by paracetamol overdose. Forty male rats (150-180 g) were maintained under normal laboratory conditions. The rats were evenly divided into four groups (10 rats per group). Group I was given distilled water; Group II was administered with a single overdose of paracetamol (3 g/kg bwt) on the 13th day of the trial; Group III was pretreated with sugarcane peel extract at a dose of 2 mL for 13 days in addition to paracetamol (3 g/kg bwt) on the 13th day, 1 hr before the treatment; while Group IV received pretreatment with silymarin (0.3 g/kg bwt) for 13 days in addition to paracetamol on the 13th day, 1 hr before the treatment. At the end of the trial (the 14th day), some biochemical parameters, as well as spleen histopathology were evaluated. The results revealed that a single overdose of paracetamol caused a significant increase in malondialdehyde, red blood cells, hemoglobin, hematocrit, and neutrophils. However, there was a significant decrease in superoxide dismutase, catalase, glutathione, total leucocyte, and platelet counts. In contrast, the administration of the extract improved these changes. The findings of this study indicated that sugarcane peel extract has great impact and potential as a cure for splenic complications from paracetamol overdose.