Background: Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease. Antirheumatoid treatment reduces disease activity and inflammation, but not all patients respond to treatment. Autonomic dysfunction is common in RA leading to frequent cardiovascular complications. Yoga therapy may be useful in these patients, but there are little data on the effect of yoga on disease activity, inflammatory markers, and heart rate variability (HRV). Objectives: This study assessed the effect of 12-week yoga therapy on disease activity, inflammatory markers, and HRV in patients with RA. Materials and Methods: This randomized control trial was conducted on newly diagnosed RA patients attending outpatient services at the Department of Clinical Immunology, JIPMER. One hundred and sixty-six participants were randomized into two groups: the control group (CG) (n = 83) and yoga group (YG) (n = 83). Yoga therapy was administered to participants in the YG for 12 weeks, along with standard medical treatment. The CG received only standard medical treatment. Primary outcomes were disease activity score 28, interleukin-1alpha (IL-1alpha), IL-6, tumor necrosis factor-alpha (TNF-alpha), cortisol, and HRV parameters. All parameters were measured at baseline and after 12 weeks. Results: Disease activity significantly decreased in both groups after 12 weeks, but it was reduced more in YG, which was statistically significant (p < 0.05). In both YG and CG, IL-1alpha, IL-6, TNF-alpha, and cortisol decreased after 12 weeks, but IL-1alpha and cortisol decreased more significantly in YG than in CG. Low-frequency component expressed as normalized unit (LFnu) and the low-frequency/high-frequency (LF-HF) ratio decreased significantly, and total power and HF component expressed as normalized unit (HFnu) increased significantly in the YG compared with CG. Conclusion: Twelve-week yoga therapy, if given along with standard medical treatment, significantly reduces disease activity and improves sympathovagal balance in RA patients.