Aim: The aim of the study was to elucidate the molecular process underlying the antimicrobial activity of Acetaminophen (APAP) and Ibuprofen (IB) against Enterococcus Faecalis (E. faecalis), Fusobacterium Nucleatum (F. nucleatum) and Peptostreptococcus Micros (P. micros) using in silico analysis. Materials and Methods: The STITCH v5.0 database was used for detecting the protein-drug interactions. The functional class and virulence property of the proteins were assessed using VirulentPred and VICMPred. PSORTb v3.0 was used to assess the subcellular localisation of virulent proteins. The epitopes were identified using BepiPred v1.0 Linear Epitope Prediction tool. Results: APAP and IB were found to interact with proteins involved in cellular processes, metabolism, virulence factors and information and storage. The virulent proteins were located in the cytoplasm and cytoplasmic membrane, which would further add to the effectiveness of these compounds to serve as potential antimicrobial agents. Finally, epitope prediction showed multiple epitopes in the virulent proteins for target specific optimization of antimicrobial agents. Conclusion: APAP and IB were found to target virulent proteins in cellular processes and metabolism of E. faecalis, F. nucleatum and P. micros with information on specific epitopes for target-aided therapeutics. To confirm the genuine interactions between the drugs and the protein repertoire of pathogens, more in vitro research on a wide range of pathogens are needed.