In this work, numerous novel 2-(p-ethyl/fluorophenyl)-5-[(p-substitutedphenyl)sulfonylamido]benzoxazole derivatives were designed, synthesized, and structurally characterized using 1H-NMR, 13C-NMR, mass spectroscopy, and elemental analysis approaches. The antimicrobial activity against several Gram (+) bacteria, Gram (−) bacteria, and fungal species was determined using the in vitro microdilution technique. A molecular docking analysis was performed on all produced compounds utilizing the S. aureus gyrase complex with ciprofloxacin and DNA. Two of the most effective compounds against S. aureus, N4 and N9, have binding energies of −8.7 kcal/mol and −8.6 kcal/mol, respectively, and their interactions have been demonstrated in 2D and 3D. Furthermore, utilizing the 6–311G(d,p) base set and DFT/B3LYP theory, MEP analysis, geometric optimization, and molecular reactivity analysis (HOMO-LUMO) of N4 and N9 were performed, and the results were presented. All compounds’ theoretical ADMET profiles were computed as well. With all of this knowledge, this study could be a pioneer in the development of novel anti-S. aureus compounds.