The electrophilic potential of vinyl sulfone permits the rapid capture of cysteine-containing proteins under physiological conditions. These cysteine proteinases play vital roles in bacterial survival and pathogenesis of Staphylococcus aureus (S. aureus) and the global health threat methicillin resistant S. aureus (MRSA). Here in, total of 28 vinyl sulfones were synthesized and subjected to susceptibility testing of pathogenic bacteria, including global epidemic MRSA PFGE strain type USA300 (SF8300). Number of antibacterial vinyl sulfone derivatives were discovered. Among these, nitrile-substituted vinyl phenyl sulfones showed potent antibacterial activity. (E)-3-((4-methoxyphenyl)sulfonyl)acrylonitrile exhibited the strongest potency with MIC of 1.875 µg/mL against methicillin susceptible S. aureus and 3.75 µg/mL against MRSA USA300. Based on the structure-activity relationship analysis, the antibacterial activity of these compounds may involve sulfhydryl conjugation. In addition, the nitrile-substituted vinyl phenyl sulfone could also impair host cell adhesion. With their promising antibacterial activities, these vinyl sulfones have potential for S. aureus and MRSA therapeutics.