The increment of Antimicrobial irrational use leads to the exacerbation of infections. The present study is designed to evaluate the antibacterial, and antioxidant activities of Guiera senigalensis ethanolic leaves extract and to determine the components of the extract for docking studies. G. senigalensis extract was used against Staphylococcus aureus ATCC25923, Escherichia coli ATCC25922, and Pseudomonas aeruginosa ATCC27853. The antimicrobial and antioxidant activities and active ingredients were determined using standard methods, computational studies were conducted via Maestro v12.8 of Schrodinger2020. Antibacterial activity of the crude extract showed that S. aureus was the most sensitive strain with MIC and MBC (12.5 and 25) mg/ml respectively followed by P. aeruginosa MIC and MBC (25 and 50) mg/ml. While E. coli was found to be resistant. In the DPPH radical scavenging assay of the extract and quercetin at concentrations (250, 125, 50, 10, and 5) µg/ml. The radical scavenging activity was 72.5%, 63.5%, 50.5%, 45.5%, and 31.3% for the extract, compared to quercetin which gave 89.7%, 85.8%, 62.1%, 55.5%, and 45% respectively. The GC-MS analysis of the total constituents revealed that 9H-Xanthene-9-one, 1,3,5,6-tetramethoxy-(28.81%), followed by phytol (22.74%), n-Hexadecanoic acid (11.3%) and 1,2,3-Benzenetriol (9.13) as major components. The docking studies of these major constituents support the antibacterial activity as they exhibited high binding affinity to UPPS targeted enzyme. Finally, this research provided useful information on the therapeutic potential of G. senegalensis. The major constituents could be considered potential antibacterial agents against S. aureus and recommended to be evaluated against MDR Bacterial strains.