Background Acetaminophen (APAP) and ibuprofen (IB) are drugs commonly used to alleviate pain due to their anti‐inflammatory, anti‐pyretic, and analgesic effect. The aim of the present study is to unravel the molecular mechanisms underlying the antimicrobial potential of these two drugs against red complex pathogens, namely, Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, by using in silico tools, since they are potentially associated with inflammatory conditions related to periodontal infections. Methods The STITCH v5.0 pipeline was primarily used for identifying drug‐protein interactions; VirulentPred and VICMPred were used for elucidating the virulence property and functional class of the proteins. The subcellular localization of virulent proteins was assessed using PSORTb v3.0 and 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 process, metabolism, and virulence. The virulent proteins targeted by the drugs were located in the cytoplasm, which would further add to the effectiveness of the drugs to serve as antimicrobial agents. Finally, epitope prediction revealed multiple epitopes in the virulent proteins which can be specifically focused on. Conclusions APAP and IB were found to target vital proteins involved in the cellular process, metabolism, and virulence of red complex pathogens. An in‐depth knowledge on the interaction of these drugs and their antibacterial activity would add to the plethora of merits gained by these drugs in clinical settings. Further in vitro studies on a wide range of pathogens are warranted to substantiate the true interactions between the drugs and the protein repertoire of pathogens.

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