Drug resistance is one of the problems affecting the world where drug-resistant Escherichia coli and Klebsiella pneumoniae have been shown to be ubiquitous, frequently isolated from foods and commonly associated with surgical site infection in hospitals worldwide. The aims of this work were to analyze the antibacterial activity of root extracts of the plant obtained by serial extraction (using petroleum ether, chloroform, methanol, and water) and by in vitro techniques and preliminary screen phytochemicals present in the extract by qualitative means. Fresh roots of Plumbago indica were collected, oven-dried, and extracted using Soxhlet apparatus; antibacterial activity, minimum inhibitory concentrations (MICs), and minimum bactericidal concentrations (MBCs) of the active extract were evaluated by standard methods against clinically isolated drug-resistant E. coli and K. pneumoniae; preliminary phytochemical screening was taken to detect the presence of alkaloids, saponins, flavonoids, steroids, tannins, reducing sugars, phenolics, protein, and oil and fat; and bioactive compounds were detected by GCMS analysis of the active extracts. Determination of antibacterial activity showed that the test organisms were susceptible to methanol and aqueous extracts only. MIC of methanolic extract was found to be 20 µg/mL on both E. coli and K. pneumoniae, while aqueous extract had MIC of 10 and 20 µg/mL on E. coli and K. pneumoniae, respectively. Preliminary phytochemical screening showed the presence of all the above-mentioned phytochemicals except oil and fat. The significance of this work is to find a lasting solution to the current problem of emerging drug-resistant bacteria (E. coli and K. pneumoniae) through the use of extracts obtained from P. indica which have long history of use as traditional medicine. The methanolic and aqueous extract can be recommended as an alternative and candidates for drug development against drug-resistant E. coli and K. pneumoniae.