Rheumatoid arthritis (RA) is a joint disorder and is considered an important public health concern nowadays. So, identifying novel biomarkers and treatment modalities is urgently needed to improve the health standard of RA patients. Factors involved in RA pathogenesis are genetic/epigenetic modification, environment, and lifestyle. In the case of epigenetic modification, the expression deregulation of microRNAs and the role of histone deacetylase (HDAC) in RA is an important aspect that needs to be addressed. The present study is designed to evaluate the expression pattern of microRNAs related to the HDAC family. Five microRNAs, miR-92a-3p, miR-455-3p, miR-222, miR-140, and miR-146a related to the HDAC family were selected for the present study. Real-time polymerase chain reaction was used to estimate the level of expression of the above-mentioned microRNAs in 150 patients of RA versus 150 controls. Oxidative stress level and histone deacetylation status were measured using the enzyme-linked immunosorbent assay. Statistical analysis showed significant downregulation (P < .0001) of selected microRNAs in RA patients versus controls. Significantly raised level of HDAC (P < .0001) and 8-hydroxy-2'-deoxyguanosine (P < .0001) was observed in patients versus controls. A good diagnostic potential of selected microRNAs in RA was shown by the receiver operating curve analysis. The current study showed a significant role of deregulated expression of the above-mentioned microRNAs in RA initiation and can act as an excellent diagnostic marker for this disease.