The phenomenon of antimicrobial resistance (AMR) has reached a critical point, threatening to render traditional antibiotics ineffective and jeopardizing decades of medical progress. At the same time, in the context of the novel coronavirus pneumonia (COVID-19) pandemic, the majority of patients receive antimicrobial treatments that may not be indicated, which may also exacerbate drug-resistant infections globally. Antimicrobial peptides (AMPs) have emerged as a promising alternative, heralding a new era in the fight against drug-resistant infections. This review provides a comprehensive overview of AMPs, demonstrating their potential to revolutionize antimicrobial therapies through unique mechanisms of action that are quite different from those of conventional antibiotics. This review provides insights into the mechanism of action of AMPs and briefly enumerates the clinical applications of AMPs. It focuses on the advances made in peptide engineering to enhance AMPs efficacy, stability and delivery. It also discusses the efficacy of AMPs against pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), mucin-resistant Escherichia coli and multidrug-resistant tuberculosis (MDR-TB). This reveals their potential to overcome current antimicrobial therapy. Furthermore, this review examines the challenges associated with the development of AMPs for clinical use, including issues related to toxicity, stability, and drug resistance. It also outlines strategies to reduce these barriers. Finally, it emphasizes the importance of innovation, interdisciplinary research, and global collaboration to advance AMPs development. Through research, AMPs will be the cornerstone of the ongoing development of antimicrobial therapies, offering hope for addressing the looming threat of drug-resistant infections.