<p>Propolis, a resinous substance collected by bees from plant sources, possesses a complex chemical composition rich in flavonoids (galangin, chrysin, quercetin), phenolic acids (caffeic, ferulic, cinnamic acid derivatives), and other bioactive compounds like artepillin C and coumaric acid. These constituents confer broad-spectrum antimicrobial activity against bacteria, viruses, fungi, and parasites. Mechanistically, propolis exerts antibacterial effects through multiple pathways: inhibiting bacterial cell wall synthesis, disrupting membrane integrity (causing ion leakage and ATP depletion), and blocking nucleic acid synthesis by targeting DNA gyrase and topoisomerase II. It also inhibits biofilm formation. Flavonoids interfere with bacterial enzymes and DNA synthesis, while artepillin C modulates inflammatory pathways, such as NF-κB, reducing prostaglandin and nitric oxide production. Propolis demonstrates synergistic effects with conventional antibiotics, enhancing their efficacy against drug-resistant strains by increasing membrane permeability and inhibiting resistance enzymes. This suggests potential for reduced antibiotic dosages and side effects, though clinical validation is still required to optimize such combinations. However, the therapeutic application of propolis faces key challenges. Its chemical composition varies by geographic origin, botanical source, and bee species complicating standardization. Extraction methods also affect the yield and potency of active compounds. Clinical data are limited, especially regarding long-term safety in immunocompromised individuals and risks of allergic reactions. Furthermore, the pharmacokinetics and molecular targets of propolis remain incompletely understood, underscoring the need for rigorous research to standardize formulations and define effective and safe therapeutic protocols.</p> Graphical Abstract <p></p>