The evolution of β-lactamases has led to threatening levels of enzyme mediated antibiotic resistance. The raise in the usage of antibiotics has decreased its effectiveness and progressed into untreatable infections. The identification of highly potential enzymes, New Delhi Metallo-beta-lactamase (NDM-1) and Extended spectrum β-lactamase (ESBL)are a menace to the public health as globally there are no clinically tested antibiotics available so far to treat such infections. Spectrum of efforts is made to combat enzyme mediated resistance by gram negative bacteria. However, very little has been achieved so far. A study was conducted where 240 medicinal plant species were screened for antibacterial activity against an NDM-1 producing E. coli strain. Twelve plant extracts displayed disruption of bacterial cell wall by scanning electron microscopy. The membrane permeability caused 79.4% to 89.7% bacterial cell deaths which was observed using flowcytometry. These potential plant extracts inhibited activity of the NDM-1 enzyme in vitro, and IC50 value ranged between 0.50 and 1.2 ng/μl while IC50 values for ESBL is yet to be estimated. Phtyocompounds from 3 plants were isolated and their combinations were checked with antibiotics and other compounds. All the active phytocompounds showed synergistic effects when combined with colistin, meropenem, and tetracycline and reduced the MIC of the tested antibiotics. Inhibition of enzyme using plant extracts or phytocompounds seems to be a promising alternate to overcome this multi drug resistance of microorganisms hence reducing the antibiotic usage. Furthermore, structural insights of the isolated compounds against these enzymes and understanding its molecular mechanisms are required before applied clinically.