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The antimicrobial peptides SAAP-148 and Ab-Cath were encapsulated in oleyl-modified hyaluronic acid (OL-HA) nanogels to improve these peptides' selectivity index. The physicochemical properties, antimicrobial activity, and cytotoxicity of the AMP-loaded OL-HA nanogels were studied in vitro. Results showed good physicochemical properties of the nanogels; polydisperse nanogels (PDI=0.2) ranging in size from 181 to 206 nm, with high negative surface charge (−47 to −48 mV) and moderate encapsulation efficiency (EE=53–63%). Encapsulation of SAAP-148 or Ab-Cath in nanogels maintained antimicrobial activity against antimicrobial resistant Staphylococcus aureus and Acinetobacter baumannii , while reducing the peptides' hemolytic activity against human erythrocytes and cytotoxicity against human primary skin fibroblasts. Thus, encapsulation in OL-HA nanogels improved the overall selectivity index of SAAP-148 and Ab-Cath and their potential as therapeutics to combat AMR bacterial infections. [Display omitted] Antimicrobial peptides (AMPs) are promising alternatives to antibiotics for treatment of antimicrobial resistant (AMR) bacterial infections. However, their narrow therapeutic window due to in vivo toxicity and limited stability hampers their clinical use. Here, we evaluated encapsulation of two amphiphilic AMPs, SAAP-148 and snake cathelicidin Ab-Cath, into oleyl-modified hyaluronic acid (OL-HA) nanogels to improve their selectivity index. The AMP-loaded OL-HA nanogels ranged 181–206 nm in size with a PDI of 0.2, highly negative surface charge (−47 to −48 mV) and moderate encapsulation efficiency (53–63%). The AMP-loaded OL-HA nanogels displayed similar activity in vitro as AMP solutions against AMR Staphylococcus aureus and Acinetobacter baumannii , with a dose-dependent effect over time. Importantly, the AMP-loaded OL-HA nanogels showed decreased cytotoxicity towards human erythrocytes and primary skin fibroblast, thereby improving the selectivity index of SAAP-148 and Ab-Cath by 2- and 16.8-fold, respectively. Particularly, the selectivity of Ab-Cath-loaded OL-HA nanogels has great clinical potential, with an index that reached ≥ 300 for S. aureus and ≥ 3000 for A. baumannii. These findings indicate that OL-HA nanogels are a promising drug delivery system to reduce the cytotoxicity of AMPs without substantially affecting their antimicrobial activity, thereby increasing their selectivity index and potential as therapeutics to combat AMR bacterial infections. [ABSTRACT FROM AUTHOR]