This trial aimed to investigate the effects of 10-week manual therapy combined with exercise compared to routine physical therapy on brain structure and clinical outcomes in patients with neck pain. Fifty-two participants with chronic nonspecific neck pain were randomized into either an intervention group or a control group (a 1:1 ratio). The intervention group received cervical mobilization and cervical and scapular exercises. The control group received routine physical therapy. The primary outcomes were cortical thickness and volume. Secondary outcomes were neck pain intensity, disability, psychological symptoms, cervical range of motion and cervical flexor muscle strength. Outcome measures were taken at baseline and post-treatment. There was no loss to follow-up. Compared to baseline, significant differences in cortical thickness were observed at post-treatment in both groups, including prefrontal cortex (PFC), anterior cingulate cortex (ACC), primary somatosensory cortex (S1), primary motor cortex (M1) and precuneus (p<
0.05). The intervention group exhibited greater increases in cortical thickness in the ACC and M1 compared to controls (p<
0.05). The secondary outcomes were improved in both groups (p<
0.05). There were differences in brain structure (S1, PFC and insula) between participants who experienced ≥50% reduction in pain intensity and those with <
50% reduction (p<
0.05). Changes in brain structure were correlated with changes in pain intensity and neck disability (r =-0.31 to -0.44, p<
0.05). The study suggests that patients with chronic nonspecific neck pain who experienced significant improvements in pain intensity exhibited greater changes in cortical structure following a 10-week intervention, particularly with a combination of manual therapy and exercise. PERSPECTIVE: A combination of manual therapy and exercise results in greater improvements in clinical outcomes and substantially alters cortical thickness compared to routine physical therapy in patients with chronic nonspecific neck pain. These findings highlight the potential impact of this intervention on both brain structure and clinical recovery.