BACKGROUND: Non-invasive treatment is generally recommended for patients with non-specific chronic low back pain (CLBP). However, the impact of combination therapy with physical exercise and a serotonin-norepinephrine reuptake inhibitor has not been clarified in patients with non-specific CLBP. This study assessed the efficacy of combination treatment with exercise and duloxetine on non-specific CLBP and aimed to identify factors that contributed to improvement of LBP-induced disability. METHODS: This prospective study was conducted on consecutive outpatients with non-specific CLBP. Patients received a supervised home-based exercise program and duloxetine administration for 15 weeks. The Roland-Morris Disability Questionnaire (RDQ), Numerical Rating Scale (NRS), Hospital Anxiety and Depression Scale (HADS), and Pain Catastrophizing Scale (PCS) were assessed at baseline and 15 weeks. Multiple logistic regression modeling was used to identify factors associated with an improvement in RDQ. RESULTS: Forty-two patients were enrolled. Overall, scores on the RDQ, NRS, and PCS (total score, magnification, helplessness) were significantly reduced at 15 weeks (p < 0.01 for all). An improvement of disability was confirmed in 22 patients (52%). A higher HADS depression score before and after the intervention was significantly associated with a lack of improvement in disability (p < 0.01). Further, a reduction in HADS anxiety score over 15 weeks was a significant factor associated with an improvement in disability (odds ratio:1.99;95% CI:1.26-3.65). CONCLUSIONS: Supervised exercise plus duloxetine resulted in favorable outcomes and an improvement of LBP-related disability in approximately 50% of patients. A reduction in anxiety over treatment was associated with the improved disability.