The emergence of multi-drug-resistant microorganisms in hospital environments is a global public health problem and threat to everyone, especially HIV-infected patients. Methicillin-resistant STAPHYLOCOCCUS aureus (MRSA) and coagulase-negative Staphylococci (CoNS) are the major causative agents associated with MORBIDITY and mortality in HIV patients. Therefore, control of MRSA and CoNS-related infections in HIV patients is a worldwide concern. To INVESTIGATE novel, potent, and cost-effective therapeutic approaches, the current study reports a simple and rapid synthesis of silver nanoparticles (AgNPs) using aqueous leaf EXTRACT of Alysicarpus monilifer and its antibacterial efficacy against multi-drug-resistant MRSA and CoNS isolates from HIV patients. The greensynthesized AgNPs were characterized using ultraviolet-visible spectroscopy, transmission electron microscopy, ENERGY dispersive X-ray analysis, selected area electron diffraction pattern, X-ray diffraction patterns, and Fourier transform infrared spectroscopy. Stable, well-defined AgNPs, mostly spherical in shape with mean size of 15 ± 2 nm, were obtained within an hour. Moreover, green synthesized AgNPs revealed significant dose-dependent antibacterial action against MRSA and CoNS isolates. This study concludes that biogenic AgNPs have demonstrated to be potent antibacterial agents in comparison with conventional antibiotics.