Exposure to drug toxicity results in stress and dysfunction of metabolizing enzymes that cause illnesses and diseases. Consumption of medicinal plant rhizomes is a regime for managing the complications. On the activities of some oxidative stress marker enzymes (catalase, glutathione, and superoxide dismutase), as well as the concentration of lipid profiles (cholesterol, triglycerides, and phospholipids) of p-hydroxyacetanilide (pPHA)-induced toxicity in rats, the effects of an aqueous extract of Curculigo pilosa (C. pilosa) rhizome were assessed. Forty rats were randomly grouped into eight groups (n = 5). The control group; aqueous extract of C. pilosa rhizome group; 750 mg/kg and 1000 mg/kg per body weight of pPHA group; the preventive groups (aqueous extract of C. pilosa rhizome and 750 mg/kg per body weight of pPHA; aqueous extract of C. pilosa rhizomes and 1000 mg/kg per body weight of pPHA); and the curative groups (750 mg/kg per body weight of pPHA and aqueous extract of C. pilosa rhizome; 1000 mg/kg body weight of pPHA and aqueous extract of C. pilosa rhizome). The oxidative stress marker enzymes and lipid profiles were analyzed spectrophotometrically in the serum, kidney, brain, and liver of the animals on the seventh and fourteenth days after the administrations. The results show that pPHA decreases the oxidative stress marker activities and the lipid profile concentrations in all the compartments, but the pre- and post-treatment with an aqueous extract of C. pilosa rhizome improved the activities of the stress marker enzymes and the lipid profiles dysfunction. The result suggests that an aqueous extract of C. pilosa rhizome has preventive and curative therapeutic potential for pPHA-induced toxicity.