Background: Cadmium (Cd) toxicity, which runs across the food chain, is chiefly regulated by in vivo antioxidant defence system or through antioxidant supplementation of biological systems predisposed to this environmental stressor. The present study was designed to examine the role of Anthocleista vogelii leaves in Cd-induced oxidative stress in the serum of Wistar rats through the application of response surface methodology (RSM) and biomonitoring of selective responses: malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), glutathione-s-transferase (GST) and peroxidase (POD) activities, respectively. The cold macerated plant leaves were subjected to fractionation process using methanol-hexane-chloroform (3:2:1 v/v) solvent system such that n-hexane fraction with ample antioxidant levels in terms of total phenolic content (TPC) and total flavonoid content (TFC) among others at p < 0.05 was selected for the study. The study employed central composite design (CCD) with twenty experimental "runs" of male Wistar rats for twenty-eight days, following a week of acclimatization, where n-hexane fraction of A. vogelii (NFAV), cadmium chloride (CdCl 2) and body weights of rats were considered input factors in the study. Results: The study generated five quadratic models, which differed significantly at p < 0.05 for MDA levels as well as CAT, SOD, GST and POD activities in the sera of Wistar rats. The study revealed that exposure to Cd toxicity caused a marked increase (p < 0.05) in serum MDA levels, but a significant inhibition (p < 0.05) of serum SOD, CAT, GST and POD activities. However, Cd interaction with NFAV showed marked amelioration of Cd-induced oxidative stress, which was confirmed by significant decrease in serum MDA levels, but significant increase in serum SOD, CAT, GST and POD activities at p < 0.05 via the response surface plots. The study also confirmed the reliability and adequacy of the models for accurate prediction of the responses since R-squared (R 2) values obtained were greater than 90%. Conclusion: It was inferred from the present study that the adequacy of the models validated the potency of A. vogelii leaves graphically in the amelioration of Cd-induced oxidative stress in the serum of Wistar rats. Hence, the plant was considered a rich source of bioactive compounds with significant antioxidant properties.