Infections caused by drug-resistant bacteria seriously endanger human health and global public health. Therefore, it is urgent to discover and develop novel antimicrobial agents to combat multidrug-resistant bacteria. In this study, we designed and synthesized a series of new membrane-active bakuchiol derivatives by biomimicking the structure and function of cationic antibacterial peptides. The most promising compound <b>28</b> displayed potent antibacterial activity against both Gram-positive bacteria (minimum inhibitory concentration, MIC = 1.56-3.125 μg/mL) and Gram-negative bacteria (MIC = 3.125 μg/mL), very weak hemolytic activity, and low cytotoxicity. Compound <b>28</b> had rapid bactericidal properties and avoided bacterial resistance. More importantly, compound <b>28</b> showed strong <i>in vivo</i> antibacterial efficacy against <i>Staphylococcus aureus</i> and <i>Pseudomonas aeruginosa</i> in murine corneal infection models. This design strategy is expected to provide an effective solution to the antibiotic crisis.