Bacterial resistance to antibiotics, first a major concern in the 1960s, has re-emerged worldwide over the last 20 years. The World Health Organization (WHO) and other health organizations have, therefore, declared 'war' against human microbial pathogens, particularly hospital-acquired infections, and have made drug discovery a top priority for these diseases. Because these bacteria are refractory to conventional chemotherapy, medicinal and herbal plants used in various countries should be assessed for their therapeutic potential; these valuable bio-resources are a reservoir of complex bioactive molecules. Earlier studies from our laboratory on Rhazya stricta, a native herbal shrub of Asia, have shown that this plant has a number of therapeutic properties. In this study, we evaluated the antimicrobial activities of various concentrations of five solvent extracts (aqueous alkaloid, aqueous non-alkaloid, organic alkaloid, organic non-alkaloid and whole aqueous extracts) derived from R. stricta leaves against several multidrug-resistant, human-pathogenic bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and extended-spectrum betalactamase-positive Escherichia coli. In vitro, molecular and electron microscopy analyses conclusively demonstrated the antimicrobial effects of these extracts against a panel of Gramnegative and Gram-positive bacteria. The organic alkaloid extract was the most effective against E. coli and MRSA, resulting in cell membrane disruption visible with transmission electron microscopy. In the near future, we intend to further focus and delineate the molecular mechanism-of-action for specific alkaloids of R. stricta, particularly against MRSA.