This study aims to develop, modify, or optimize potent active compounds by utilizing combinatorial synthetic methods involving phytoconstituents from plant extracts to enhance efficacy and reduce resistance potential. We employed ATR-FTIR, GC-MS, and antibacterial results from related literature to validate these strategies. The methodology involved careful harvesting, pre-treatment, and extraction processes to ensure the quality and efficacy of plant extracts. We used various extraction methods and solvents to isolate specific phytoconstituents, followed by further purification using chromatography. The study proposes three strategies: (1) reacting single or multiple plant extracts with reagents like acids or catalysts, (2) combining plant extracts with ineffective drugs to induce structural changes that enhance antibacterial efficacy, and (3) combining plant extracts with drugs not originally intended for the target disease to explore new structural functionalities. Notable results included the synergistic effects observed in combining Psidium guajava and Calotropis procera extracts with antibiotics, significantly increasing zones of inhibition against resistant bacteria. GC-MS analysis identified numerous bioactive compounds, some with known anticancer properties, suggesting potential applications beyond antibacterial effects. Our findings demonstrate that these innovative combinatorial approaches can yield new compounds with enhanced antimicrobial properties, highlighting the potential of plant extracts in drug discovery and development. This study underscores the promise of harnessing natural products to combat multi-drug resistance, paving the way for advanced research and development in pharmaceutical applications.