Abstract The global rise of multidrug-resistant (MDR) infections highlights the urgent need for innovative therapeutic strategies beyond traditional antibiotics. Antimicrobial peptides (AMPs), naturally occurring in all forms of life and synthetically producible, have garnered significant attention for their broad-spectrum antimicrobial properties and diverse mechanisms of action, including membrane disruption, immune modulation, and biofilm formation inhibition and disruption. Despite great potential, the clinical deployment of AMPs faces significant challenges, including cytotoxicity, low chemical stability, high production costs, and stringent regulatory demands. Innovative strategies, such as AMP-antibiotic conjugation, offer potential solutions to some of these challenges by enhancing efficacy, reducing toxicity, and broadening antimicrobial activity. This review critically evaluates the promise and limitations of AMPs as therapeutic antibacterial agents. We also explore the potential of AMP-antibiotic conjugates, highlighting their potential synergistic effects and the obstacles to their clinical application. Antimicrobial self-assembling peptides are also discussed, with their ability to form nanostructures that may disrupt biofilms and inhibit bacterial communication, representing a promising but complex avenue. A critical perspective on the challenges and practical applicability of these strategies is essential to advance their development in the fight against antimicrobial resistance.