The unprecedented use of antibiotics that led to development of resistance affect human health worldwide. Prescription of antibiotics imprudently and irrationally in different diseases progressed with the acquisition and as such development of antibiotic resistant microbes that led to the resurgence of pathogenic strains harboring enhanced armors against existing therapeutics. Compromised the treatment regime of a broad range of antibiotics, rise in resistance has threatened human health and increased the treatment cost of diseases. Diverse on metabolic, genetic and physiological fronts, rapid progression of resistant microbes and the lack of a strategic management plan have led researchers to consider plant-derived substances (PDS) as alternative or in complementing antibiotics against the diseases. Considering the quantitative characteristics of plant constituents that attribute health beneficial effects, analytical procedures for their isolation, characterization and phytochemical testing for elucidating ethnopharmacological effects has being worked out for employment in the treatment of different diseases. With an immense potential to combat bacterial infections, PDSs such as polyphenols, alkaloids and tannins, present a great potential for use, either as antimicrobials or as antibiotic resistance modifiers. The present study focuses on the mechanisms by which PDSs help overcome the surge in resistance, approaches for screening different phytochemicals, methods employed in the identification of bioactive components and their testing and strategies that could be adopted for counteracting the lethal consequences of multidrug resistance.