Background Through the bioinformatics analysis to screen out the potential chromatin regulators (CRs) under the immune infiltration of osteoarthritis (OA), thus providing some theoretical support for future studies of epigenetic mechanisms under OA immune infiltration. Methods By integrating CRs and the OA gene expression matrix, we performed weighted gene co-expression network analysis (WGCNA), differential analysis, and further screened Hub genes by protein-protein interaction (PPI) analysis. Using the OA gene expression matrix, immune infiltration extraction and quantification were performed to analyze the correlations and differences between immune infiltrating cells and their functions. By virtue of these Hub genes, Hub gene association analysis was completed and their upstream miRNAs were predicted by the FunRich software. Moreover, a risk model was established to analyze the risk probability of associated CRs in OA, and the confidence of the results was validated by the validation dataset. Results This research acquired a total of 32 overlapping genes, and 10 Hub genes were further identified. The strongest positive correlation between dendritic cells and mast cells and the strongest negative correlation between parainflammation and Type I IFN reponse. In the OA group DCs, iDCs, macrophages, MCs, APC co-inhibition, and CCR were significantly increased, whereas B cells, NK cells, Th2 cells, TIL, and T cell co-stimulation were significantly decreased. The risk model results revealed that BRD1 might be an independent risk factor for OA, and the validation dataset results are consistent with it. 60 upstream miRNAs of OA-related CRs were predicted by the FunRich software. Conclusion This study identified certain potential CRs and miRNAs that could regulate OA immunity, thus providing certain theoretical supports for future epigenetic mechanism studies on the immune infiltration of OA.