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This research was borne out of finding alternatives to antibiotics. In this study, Pleurotus ostreatus and Pleurotus pulmonarius were cultivated using cassava peels and sawdust of Tectonia grandis. The mushrooms utilized the lignocellulose in the agro-wastes to grow within 30 days and the antimicrobial potency of the harvested mushrooms was investigated. P. ostreatus and pulmonarius extracts were assayed against seven pathogenic bacteria: Staphylococcus aureus, Streptococcus pyogenes, Klebsiella pneumoniae, Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa and Aeromonas hydrophilia using Kirby Bauer's agar well diffusion. The result of sensitivity test showed that all test organisms except A hydrophilia were susceptible to the ethanoilic extract of P. ostreatus while most were resistant to P. pulmonarius. The In vitro bioassay revealed that the aqueous extract of P. ostreatus inhibited S. aureus, K. Pneumoniae, E. coli, P. aeruginosa, B. subtilis and S. pyogenes with inhibition zones of 18.00 ±0.24 mm, 16.00 ±0.15 mm, 14.00 ±0.05 mm, 14.50 +0.12 mm, 15.10 + 0.20 mm and 17.00 ± 0.22 mm respectively. Phytochemical assays showed that P. ostreatus contained some essential phytochemicals which include; alkaloids, tannins, saponins and phenol of which some were present in P. pulmonarius. The results obtained suggest that P. ostreatus grown on the mixture of these two substrates (cassava peels and sawdust of T. grandis) possessed broader antimicrobial spectrum against a vast numbers of medically implicated organisms used, hence future research work is required to consolidate the potency of mushrooms cultivated on these substrates.