INTRODUCTION: Chronic low back pain (CLBP) is a prevalent and debilitating condition. Cognitive behavioral therapy (CBT) can improve coping mechanisms for CLBP and pain-related outcomes. However, the mechanisms by which they do so remain undetermined. We explored the neural correlates of CLBP symptoms and CBT action using functional magnetic resonance imaging (fMRI) in women with CLBP and comorbid depression. METHODS: Forty individuals underwent fMRI followed by 8 weeks of either treatment as usual (TAU) or one of two CBT in addition to TAU: acceptance and commitment therapy (ACT) or behavioral activation treatment for depression (BATD). Pain intensity, depression, psychological inflexibility, and pain catastrophizing scores were obtained at baseline and follow-up. Functional connectivity (FC) patterns of the salience network (SN), sensorimotor network (SMN), and the mesolimbic pathway (MLP), derived from resting-state fMRI examination were correlated with both baseline and delta (baseline-follow-up) pain-related psychological measures. RESULTS: Individuals receiving ACT and BATD showed reduced depression, psychological inflexibility, and pain catastrophizing. Strong baseline connectivity of the SN and SMN corresponded with higher pain intensity, but strong connectivity of the MLP and precuneus corresponded with lower pain intensity. Pain intensity changes correlated with mesolimbic-salience connectivity following ACT, and with sensorimotor connectivity following BATD. Specifically, stronger baseline FC between the MLP and posterior insula predicted greater pain intensity reduction with ACT, while stronger FC between the SMN and secondary somatosensory cortex predicted greater pain intensity reduction with BATD. FC of the SN correlated with changes in psychological inflexibility across both therapies. CONCLUSIONS: We illustrate the potential of FC as a biomarker of CLBP plus depression and the response to CBT. Our data suggest ACT and BATD have differing underlying brain mechanisms. These findings indicate that FC biomarkers could guide personalized treatment, improving individual outcomes.