Drug-resistant infections represent one of the most pressing challenges in modern medicine, forcing researchers to explore novel therapeutic strategies beyond traditional antibiotics. The emerging field of host-directed therapy offers a promising alternative by strengthening the body's own defense mechanisms rather than directly attacking pathogens. A comprehensive review in Autophagy examines how naturally occurring compounds might harness autophagy—the cellular process by which cells break down and recycle their components—to enhance antimicrobial responses. The analysis reveals that diverse natural products, including polyphenols from plants, alkaloids, terpenoids, quinones, peptides, and macrolides, can either activate or inhibit autophagy pathways depending on the specific pathogen and infection context. These compounds demonstrate effectiveness against bacterial, viral, fungal, and parasitic infections through multiple mechanisms beyond direct autophagy modulation. The research highlights a critical complexity in this therapeutic approach: while autophagy activation generally strengthens immune responses and reduces harmful inflammation, some pathogens have evolved to exploit these same cellular recycling pathways for their own survival and replication. This dual nature means that autophagy-targeting therapies require precise calibration based on the specific infectious agent. The findings suggest that natural autophagy modulators could serve as valuable adjuncts to conventional treatments, potentially overcoming resistance mechanisms that have rendered many antibiotics ineffective. However, the review underscores the need for deeper mechanistic understanding to distinguish between direct autophagy effects and indirect benefits through immune enhancement or organelle interactions, emphasizing that successful translation to clinical applications will require careful pathogen-specific optimization.