This study explored the antimicrobial potential of Piper betle L. (PBL) and Piper nigrum L. (PNL) extracts against MRSA. Plant parts including stem, leaf, and fruit were extracted using aquadest, methanol, and hexane, resulting in 18 distinct extracts. FT-IR combined with cluster analysis (CA) categorized the extracts, and anti-MRSA activity was assessed through the paper disk diffusion method. The most potent extracts were further analyzed using GC-MS to identify bioactive compounds. Additionally, molecular docking studies were conducted for MRSA protein targets (4DKI, 6H5O, and 4CJN). The hexane extract of PNL and the aqueous extract of PBL fruit showed the strongest inhibitory effects. GC-MS identified piperine (14.22%) and diisooctyl phthalate (14.67%) as major compounds, with piperolein B, piperanine, β-caryophyllene oxide, and α-caryophylladienol as minor compounds in the hexane extract of PNL, while hydroxychavicol (81.89%) and chavibetol (12.01%) were predominant in the aquadest extract of PBL. Molecular docking revealed that piperolein B and piperine had strong binding affinities to MRSA proteins 4DKI, 6H5O, and 4CJN, comparable to ciprofloxacin. In conclusion, this study confirms the potential of PBL and PNL as sources of novel anti-MRSA agents, supporting further research to develop new therapies.