Acalypha wilkesiana is a tropical plant used to treat a wide range of medical conditions. The leaves of A. wilkesiana were tested for phytochemicals with microbicide activity against a variety of microorganisms known to cause severe human infections. Antimicrobial efficacy of essential oil extracts from pulverised dried leaves of A. wilkesiana was examined. Phytochemical and proximate assessments of the leaves were carried out using standard techniques. The essential oil was extracted using hydro-distillation and collected using two processes. The first form was extraction for four hours straight, and the second mode involve hourly collection for four times. A total of five fractions of the essential oil were extracted. The chemical constituent of the oil was separated with Gas chromatography–mass spectrometry (GC-MS) in accordance with standard procedures. The proximate composition of leaves showed low moisture and high carbohydrate (61.39%). Tannins, flavonoids, and alkaloids were among the secondary metabolites found in the leaves. Six bioactive compounds including n-Hexadecanoic acid and 6-Benzamido-4-benzoyl-1, 2, 4-triazine-3, 5 were identified in the GC–MS analysis. The oils from A. wilkesiana leaves have excellent broad-spectrum antimicrobial activity at various concentrations on Staphylococcus species, Bacillus coagulans, Escherichia coli, Klebsiella pneumoniae, Salmonella typhimurium and Candida albicans. It could not, however, inhibit the growth of Pseudomonas aeruginosa and Gardnerella vaginalis. The findings justify the usage of A. wilkesiana leaves in ethnomedicine for possible management of skin conditions, gastrointestinal problems as well as other related microbial infections.