Antibiotic resistance is emerging as a "global public health concern". To address the growing epidemic of multidrug-resistant pathogens, the development of novel antimicrobials is urgently needed. In this study, by biomimicking cationic antibacterial peptides, we designed and synthesized a series of new membrane-active nonivamide and capsaicin derivatives as peptidomimetic antimicrobials. Through modulating charge/hydrophobicity balance and rationalizing structure-activity relationships of these peptidomimetics, compound <b>51</b> was identified as the lead compound. Compound <b>51</b> exhibited potent antibacterial activity against both Gram-positive bacteria (MICs = 0.39-0.78 μg/mL) and Gram-negative bacteria (MICs = 1.56-6.25 μg/mL), with low hemolytic activity and low cytotoxicity. Compound <b>51</b> displayed a faster bactericidal action through a membrane-disruptive mechanism and avoided bacterial resistance development. Furthermore, compound <b>51</b> significantly reduced the microbial burden in a murine model of keratitis infected by <i>Staphylococcus aureus</i> or <i>Pseudomonas aeruginosa.</i> Hence, this design strategy can provide a promising and effective solution to overcome antibiotic resistance.