Background Croton membranaceus Müll.Arg., root extract has been scientifically and clinically proven to be efficacious in the management of BPH. However, its effect on liver drug-metabolizing enzymes has not been established. This study aimed to determine the effect of the plant extract on phase I and phase II drug-metabolizing enzymes. Materials and methods Fifteen (15) castrated testosterone-induce BPH male Albino Wister rats weighing between 120–150 grams were randomly divided into 3 groups of 5 rats each (Groups II-IV). Five (5) uncastrated rats in Group I was used as a negative control, receiving only distilled water. Group II was administered 30 mg/kg b. wt extracts of C. membranaceus. Group III was the BPH-model group (administered distilled water) while Group IV was administered 0.5 mg/kg b. wt finasteride and was used as the positive control. BPH was induced in groups II-IV by administering testosterone propionate, 3 mg/kg b. wt for 28 days after a 7-day post castration rest period. Rats were euthanized and individual livers harvested for microsome preparation. The liver microsomes were assayed for, Phase I Drug Metabolizing Enzymes (DME); CYP1A2, CYP3A4, CYP2D6, and phase II; GST-M1 using Enzyme-Linked Immuno-Sorbent Assay (ELISA) techniques. Results Significant induction in phase I enzymes CYP1A2 was observed (p = 0.02), while CYP3A4 and CYP2D6 were inhibited (0.00, 0.01, respectively). Phase II enzymes, GSTM1, showed a significant induced (p = 0.01). C.membranaceus induced CYP1A2 strongly, GSTM1 modestly, and had an inhibitory effect on CYP3A4/CYP2D6. Conclusion Croton membranaceus induces and inhibits some phase I metabolizing enzymes while moderately inducing phase II metabolizing enzymes. Care should be taken in the use of phytotherapy in conjunction with other drugs.