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Introduction. Yersinia enterocolitica is one of the leading food-borne entero-pathogens causing various illnesses ranging from gastroenteritis to systemic infections. Quorum sensing (QS) is one of the prime mechanisms that control the virulence in Y. enterocolitica . Hypothesis/Gap Statement. Vanillic acid inhibits the quorum sensing and other virulence factors related to Y. enterocolitica . It has been evaluated by transcriptomic and Insilico analysis. Therefore, it can be a prospective agent to develop a therapeutic combination against Y. enterocolitica . Aim. The present study is focused on screening natural anti-quorum-sensing agents against Y. enterocolitica . The effect of selected active principle on various virulence factors was evaluated. Methodology. In total, 12 phytochemicals were screened by swarming assay. MATH assay, EPS and surfactant production assay, SEM analysis, antibiotic and blood sensitivity assay were performed to demonstrate the anti-virulence activity. Further, RNA sequencing and molecular docking studies were carried out to substantiate the anti-QS activity. Results. Vanillic acid (VA) has exhibited significant motility inhibition, thus indicating the anti-QS activity with MQIC of 400 µg ml−1 without altering the cell viability. It has also inhibited the violacein production in Chromobacterium violaceum ATCC 12472, which further confirms the anti-QS activity. VA has inhibited 16 % of cell-surface hydrophobicity (CSH), 52 % of EPS production and 60 % of surfactant production. Moreover, it has increased the sensitivity of Y. enterocolitica towards antibiotics. It has also made the cells upto 91 % more vulnerable towards human immune cells. The transcriptomic analysis by RNA sequencing revealed the down regulation of genes related to motility, virulence, chemotaxis, siderophores and drug resistance. VA treatment has also positively regulated the expression of several stress response genes. In furtherance, the anti-QS potential of VA has been validated with QS regulatory protein YenR by in silico molecular simulation and docking study. Conclusion. The present study is possibly the first attempt to demonstrate the anti-QS and anti-pathogenic potential of VA against Y. enterocolitica by transcriptomic and in silico analysis. It also deciphers that VA can be a promising lead to develop biopreservative and therapeutic regimens to treat Y. enterocolitica infections.