Prosopis africana, a chewing stick popularly used in the South Western part of Nigeria was examined for antimicrobial activity against Lactobacillus casei ATCC 334, Staphylococcus aureus ATCC 35218, Candida albicans ATCC 10231, Escherichia coli ST2747 and Streptococcus mutans using agar well diffusion method. Extraction was done using ethanol and distilled water. The plant was screened for its phytochemical components. Gas chromatography mass spectrometry analysis was done to detect the secondary metabolites. All the extracts showed antimicrobial activity against the organisms with zones of inhibition ranging from 3.33±0.29-13.83±1.61 mm except Staphylococcus aureus ATCC 35218 which was resistant to aqueous extract of the dried sample. Statistical analysis of data showed that there was no significant difference in the antimicrobial effects of ethanolic and aqueous extracts of the plant samples at 95% confidence intervals. The phytochemical screening result showed that phenols, alkaloids, sterols, triterpenes and saponins are components of the chewing stick. Also, fatty acids such oleic, palmitic and stearic acids were chemical constituents detected in the plant extracts by GC-MS. The results obtained in this study indicate that P. africana will be useful in the treatment of oral infections.