Over the years, antimicrobial resistance (AMR) and multidrug resistance (MDR) have become a global threat to universal health. Emergence of AMR and MDR has led to a decline in the efficacy of conventional antibiotics against bacterial and fungal infections. The current chapter investigates the prospective of medicinal plants and their phytocompounds as synergistic agents that enhance the activities of the currently employed antibiotics. Medicinal plants produce secondary metabolites, including flavonoids, alkaloids, and terpenoids, and exhibit multiple mechanisms of synergy, including disruption of microbial membranes, inhibition of resistance-related enzymes and efflux pumps, and suppression of biofilm formation. Combining these natural agents with antibiotics not only enhances antimicrobial efficacy but also lowers the minimum inhibitory concentrations (MICs), delays resistance development, and minimizes adverse drug effects. Evidence from numerous studies demonstrates the effectiveness of such combinations against various MDR pathogens, including Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Neisseria gonorrhoeae, and Candida species. This chapter highlights molecular mechanisms, examples of successful plant–antibiotic combinations, and therapeutic implications. Despite promising results, challenges such as standardization, clinical validation, and safety concerns remain. Future perspectives emphasize the need for in vivo studies, clinical trials, and regulatory frameworks to ensure the safe integration of plant-based adjuvants in antimicrobial therapy. Overall, synergistic use of medicinal plants and antibiotics offers a sustainable and innovative approach to combat resistant infections.