Background <p>Antimicrobial resistance (AMR) is a growing global health challenge, threatening the efficacy of existing antibiotics and demanding urgent attention to mitigate its impact.</p> Methods <p>Addressing this crisis requires innovative therapeutic approaches, and macromolecules have gained significant attention as potential solutions. Biomacromolecules, particularly antimicrobial peptides (AMPs), have emerged as structurally distinct agents capable of circumventing conventional resistance mechanisms.</p> Results <p>This review emphasizes the structure–function relationships of AMPs, detailing how their amphipathic architectures, cationic charge distributions, and secondary structural motifs (e.g., α-helices, β-sheets) underpin their selective interactions with bacterial membranes, biofilms, and intracellular targets. Mechanistic insights into pore-forming models, non-lytic membrane disruption, and intracellular modulation are critically examined to highlight the therapeutic versatility of AMPs.</p> Discussion <p>We also explore delivery strategies and polymeric conjugates that enhance AMP stability, bioavailability, and targeting efficiency.</p> Conclusion <p>By consolidating current understanding of AMP structural biology and mechanistic action, this review provides a focused framework for the rational design of next-generation macromolecular antimicrobials to address the escalating AMR crisis.</p> Graphical Abstract <p></p>