Knee osteoarthritis (KOA) is a common degenerative joint disease with unsatisfactory treatment. Recently, non-pharmacological therapies, such as physical exercise and mind-body exercises, have received considerable attention for their implications in pain management in KOA. However, the mechanisms underlying the efficacy of different exercises on pain improvement remain unclear. In this study, we investigate the effect and underlying mechanisms of mind-body exercises (Tai Chi Chuan and Baduanjin) and physical exercise (stationary cycling) in patients with knee osteoarthritis (KOA). One hundred and forty patients were randomized into Tai Chi Chuan, Baduanjin, stationary cycling, and health education control groups for 12 weeks. The Knee injury and Osteoarthritis Outcome Score (KOOS), resting-state functional connectivity (rsFC) of the cognitive control network (CCN), and blood markers [serum Protectin D1 (PD1) and brain derived neurotrophic factor (BDNF) levels] were measured at the beginning and end of the experiment. We also applied support vector machines regression to predict the effectiveness of different exercises on KOA patients based on rsFC of CCN. We found: –KOOS pain subscores and serum PD1 levels significantly increased in all three exercise groups compared to the control group, and there were no significant differences among the three exercise groups; –rsFC between the bilateral dorsal lateral prefrontal cortex (DLPFC) and bilateral supplementary motor area (SMA) and temporoparietal junction (TPJ) was significantly decreased in all exercise groups compared to control group, and the decreased DLPFC-SMA rsFC was significantly associated with improvements in knee pain and serum PD1 levels across all subjects at baseline; –baseline DLPFC-SMA rsFC can significantly predict the effect of exercise on pain improvement in KOA patients. Conclusion: Our findings demonstrate different exercises may achieve clinical improvements through shared pathways and highlight the potential of neuroimaging biomarkers for predicting the therapeutic effect of exercises on KOA pain.