Acacia Brevispica Harms is one of the medicinal plants widely distributed in low land of Ethiopia. The leaves of this plant possess various medicinal properties such as of headache and Cancer related fever (Hyperpyrexia). Therefore, this study was aimed to evaluate the antimicrobial activity of the leaves and screen major phytochemical constituents present within the plants responsible for those activities. The plant leaves were extracted successively with petroleum ether, chloroform and ethanol. Accordingly, a crude yield of 0.38% from petroleum ether, 0.47% from chloroform and 8.5% (w/w) from ethanol were extracted. The phytochemical analysis showed the presence of steroids and anthraquinones in all ethanol, chloroform and petroleum ether crude extracts. The phytochemical analysis also indicated the presence of flavonoids and phenol in ethanol extract, alkaloid in chloroform, terpenoids in petroleum ether and carbohydrates in both chloroform and petroleum ether crude extracts. The antimicrobial activity of the crude extracts was determined by agar diffusion method. The ethanol extracts exhibited relatively higher zone of inhibition (6.42 ± 0.13 mm) against Escherchia coli and Salmonella typhus (6.37 ± 0.08 mm) 5.26 ± 0.08 mm) as compared to chloroform extract (5.33 ± 0.07 mm against Escherchia coli and 5.26 ± 0.08 mm Salmonella typhus). Chloroform extract also showed. The results indicated that Acacia brevispica could be used as a source of antimicrobial agents to treat various diseases.