Antibiotic resistance has greatly endangered the global public health system and seriously endangered human health. It is urgent to discover and develop new antibacterial agents against multidrug-resistant bacterial infection. In this study, we designed and synthesized a series of amino acid modified bakuchiol derivatives as membrane-active antibacterial agents by biomimicking the chemical structure and biological function of cationic antibacterial peptides. Through the structure-activity relationship study, we obtained the two promising compounds BK69 and BK79, which showed excellent antibacterial activity against both gram-positive and gram-negative bacteria (MICs=0.78-3.125 μg/mL), extremely poor hemolytic activity (HC50>400 μg/mL) and very low cytotoxicity. Compounds BK69 and BK79 could achieve rapid sterilization by directly destroying the bacterial cell membrane, and effectively avoided the development of bacterial resistance in laboratory simulations. It is worth noting that compounds BK69 and BK79 shows excellent broad-spectrum in vivo efficacy in murine corneal and skin infection models. More importantly, compound BK69 shows good pharmacokinetic properties and has an effective antibacterial effect in a murine fatal peritonitis model. This design strategy provides an effective solution to the crisis of antibiotic resistance.