This study investigated the hepatoprotective and antioxidant response to intraperitoneal, intravenous, subcutaneous and oral treatment with quercetin in adult male Wistar rat. The animals were divided randomly into the four groups according to the routes of administration. Quercetin was allowed to react with selected hepatic isoenzymes (aspartate amino transferase, alanine amino transferase) via administration of quercetin at a dose of 50 mg/kg (once/day) for 5 days through different routes (oral, intravenous, intraperitoneal, subcutaneous) to adult male Wistar rats. The plasma hepatic enzyme activities and non-enzymatic antioxidant indices (total phenol, flavonoids, and vitamin C) were quantified spectrophotometrically. Ex vivo study showed that the enzymatic activity of AST and ALT was significantly decreased (p<0.001) irrespective of the routes of administration when compared with the standard (control). The plasma non-enzymatic antioxidant indices like phenol, flavonoid except vitamin C were all significantly increased (p<0.001) irrespective of the routes of administration when compared with the standard (control). Parenteral routes of administration showed significant hepatoprotective and antioxidant response compared to the oral route of administration. Quercetin has more capacity to initiate tissue repair, or minimize cellular damage or injury that could lead to hyperactivity of the hepatic enzymes, and enhance the body antioxidant defence mechanism through the parenteral routes of administration.