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A number of pathogenic bacteria reproduce inside mammalian cells and are thus inaccessible to many antimicrobial drugs. Herein, we present a facile method to a focused library of antibacterial agents known as cationic amphiphilic polyproline helices (CAPHs). We identified three CAPHs from the library with superior cell penetration within macrophages and excellent antibacterial action against both Gram-positive and Gram-negative bacteria. These cell-penetrating antibacterial CAPHs have specific subcellular localizations that allow for targeting of pathogenic bacteria at their intracellular niches, a unique feature that promotes the successful clearance of intracellular pathogens (Salmonella, Shigella, and Listeria) residing within macrophages. Furthermore, the selected CAPHs also significantly reduced bacterial infections in an in vivo model of Caenorhabditis elegans, with minimal in vivo toxicity.