Introduction: The idea that certain plants had healing potential was known long before human beings discovered the existence of pathogens. Methodology: The crude methanolic leaf extract of Prosopis africana was assayed for antimicrobial potency using Agar-well diffusion technique against Salmonella typhi, Klebsiella pneumoniae, Streptococcus pyogenes, Pseudomonas aeruginosa, Methicillin-Resistant Staphylococcus aureus (MRSA) and Candida albicans. Qualitative phytochemical screening was also carried out. Results: The results of the antimicrobial screening showed antimicrobial potency against the test isolates with various degrees of zone of inhibition which varied between 10 mm – 22 mm. The highest zone was reported against Klebsiella pneumoniae (22 mm), followed by Streptococcus pyogenes and Candida albicans (21 mm), Salmonella typhi (20 mm), MRSA (19 mm) and then Pseudomonas aeruginosa (18 mm). Chloramphenicol and Fluconazole are used as reference standard and their zones of inhibitions ranged from 26 mm – 29 mm. The Minimum Inhibitory Concentration (MIC) of the extract ranged between 12.50 mg/mL – 50.00 mg/mL whilst the Minimum Bactericidal Concentration (MBC) and Minimum Fungicidal Concentration (MFC) of the extract were at 50.00 mg/mL. The result of phytochemical screening revealed the presence of carbohydrates, flavonoids, phenols/tannins, saponins, terpenes, steroids, cardiac glycosides and alkaloids as secondary metabolites. Conclusion: The findings clearly showed that methanolic leaf extract of P. africana has proved its use in folklore as an alternative antimicrobial agent and further research can lead to isolation of a new lead of medical importance.