The phytochemical screening and in-vitro antimicrobial activities of methanolic leaf extract of Cnidoscolus aconitifolius were investigated. The proximate analysis showed that the leaves contained moisture (5.35%), ash (13.69%), crude protein (18.74%), fat (11.95%), fibre (9.81%) and carbohydrate (40.48%). The mineral analysis in mg/100g indicated that leaves contained Sodium (77.32), Potassium (58.45), Calcium (44.82), Magnesium (23.46), Zinc (0.02), Copper (0.004), Iron (0.06) while Lead was absent. The phytochemicals present in the leaves of C. aconitifolius were alkaloids, tannins, saponin, flavonoids and cardiac glycoside while steroids, phlobatannin and terpenoids were not detected. Antimicrobial activities were assayed using the concentrations of 500, 250, 125, 62.5 and 31.25mg/ml. The antibacterial effects of the extract showed that Klebsiella pneumonia had a zone of inhibition that varied from 1.0mm (125mg/ml) to 4.5mm (500mg/ml), Psuedomonas aeruginosa with a zone of inhibition of 1.5mm (125mg/ml) to 5.0mm (500mg/ml), similarly, Escherichia coli had a zone of inhibition of 1.0mm (125mg/ml) to 3.5mm (500mg/ml). Staphylococcus aureus had a zone of inhibition of 1.0mm (62.5mg/ml) to 6.5mm (500mg/ml). However, all test bacteria were resistant to the extract at lower concentrations of 31.25mg/ml and 62.5mg/ml except S. aureus. The effect of methanolic extract of C. aconitifolius on radial mycelial growth of the test fungi after varied hours of incubation showed that Aspergillus tamari had a percentage inhibition that ranged from 22% (31.25mg/ml) to 100% (500mg/ml) at 24hrs, similarly it had a percentage inhibition of 12% (31.25mg/ml) to 76% (500mg/ml) at 72hrs. A. niger had a percentage inhibition of 9% at 31.25mg/ml to 91% at 500mg/ml after 24hrs, but it completely inhibited the growth at 31.25mg/ml and 72% at 500mg/ml after 72hrs of incubation. This study showed that C. aconitifolius could be a potential antimicrobial agent for the treatment of infections and a good dietary source of nutrients.