Salmonella Typhi is a major global concern in many low- and middle-income countries. In addition, the emergence and persistence of drug resistant strains has increased the impact of this disease. Plant metabolites have been explored traditionally and scientifically as antimicrobial agents. Thus, this study was designed to investigate the antimicrobial potential of acetone leaf fractions of H. indica against S. Typhi. Dried pulverized leaves of H. indica were extracted using cold maceration with acetone after defatting with n-hexane. The leaf extract was concentrated and subjected to column chromatography and eight bioactive fractions were identified. The fractions were characterized using gas chromatography-mass spectrometry. The fractions were evaluated for antibacterial activity against Salmonella Typhi in-vitro and in-silico. The lowest MIC was observed in fractions 20 and 21 (0.375 mg/mL) while the lowest MBC was observed in all fractions except 7, 17 and 18 (0.375 mg/mL). A ligand from fraction 8 had the highest binding affinity to Type I dehydroquinase (-3.4) and a ligand from fraction 7 had the highest binding affinity to Gyrase B (-11.2). This study concludes that the overall antimicrobial activity of the acetone leaf extract of H. indica provided evidence that it contains drug-like compounds that can be further explored as a drug candidate against S. Typhi.