Nowadays, the infection caused by the methicillin-resistant Staphylococcus aureus (MRSA) and countless different types of bacterial infection cause the death of millions of people worldwide. Thereby, several strategies have explored for the advancement of better and active antimicrobial agents; one of these lies in the form of two-dimensional carbon-based nanocomposites. Herein, we demonstrate the synthesis of the graphene-polyindole (Gr@PIn) nanocomposite and polyindole (PIn) and significantly enhance the proficiency against MRSA strains which are immune to most antibiotics. The synthesized Gr@PIn and PIn have been characterized by the various biophysical techniques, especially X-ray diffraction (XRD), electron microscopy [scanning electron microscopy (SEM) and transmission electron microscopy (TEM)], Fourier transform infrared, Raman, UV-vis spectroscopy, and thermogravimetric analysis. Electron microscopic investigations unveiled the disintegration of bacterial cell wall upon interaction with Gr@PIn. Significantly, the Gr@PIn found to be very potent in the eradication of the MRSA strain with minimal toxicity to the mammalian cells. Assessment of the antibacterial mechanism revealed that the Gr@PIn adhered toward the bacterial surface, irreversibly interrupted the membrane layer structure of the bacteria, eventually penetrated cells, and efficiently impeded protein activity, which inherently turns into bacterial apoptosis in vitro. Moreover, last, the synthesized Gr@PIn efficiently treated the S. aureus-mediated experimental skin infection in BALB/c mice as well. This work magnifies our comprehending antibacterial mechanism of nonmetallic graphene-based PIn nanocomposite and provides the support to activity anticipation.