Due to the emergence of antimicrobial resistance and the lack of new antibacterial agents, it has become urgent to discover and develop new antibacterial agents against multidrug-resistant pathogens. Antimicrobial peptides (AMPs) serve as the first line of defense for the host. In this work, we have designed, synthesized, and biologically evaluated a series of phenyl sulfide derivatives by biomimicking the structural features and biological functions of AMPs. Among these derivatives, the most promising compound <b>17</b> exhibited potent antibacterial activity against Gram-positive bacteria (minimum inhibitory concentrations = 0.39-1.56 μg/mL), low hemolytic activity (HC<sub>50</sub> > 200 μg/mL), and high membrane selectivity. In addition, <b>17</b> can rapidly kill Gram-positive bacteria within 0.5 h through membrane-targeting action and avoid antibiotic resistance. More importantly, <b>17</b> showed high in vivo efficacy against <i>Staphylococcus aureus</i> in a murine corneal infection model. Therefore, <b>17</b> has great potential as a lead compound for the treatment of Gram-positive bacterial infections.