Background: Spinal manipulative therapy (SMT) demonstrates small effects on pain intensity in low back pain. Combining SMT with a psychosocial intervention like pain neuroscience education (PNE) could promote additional effect. Objectives: To evaluate the additional effect of PNE when combined to SMT on pain intensity and low back pain-related disability in patients with chronic low back pain (CLBP). Method: One hundred and four patients with CLBP of both sexes aged between 18 and 55 years were treated with PNE + SMT compared to SMT alone. The primary outcome measures were pain intensity and disability post-treatment (4 weeks). Secondary outcomes were fear-avoidance beliefs, global perceived effect of improvement, and pain self-efficacy. Results were obtained immediately post-treatment and at three follow-ups (30-days, 90-days, and 180-days). Results: No significant between-group difference was observed for pain intensity and disability post-treatment. In contrast, our results showed a significantly longer additional effect for the group treated with SMT + PNE for the following outcomes: pain intensity (change baseline to 90 day follow-up = -0.90 [95% CI= -1.76, -0.4] and change baseline to 180 day follow-up = -1.19 [95% CI= -2.06, -0.32]) and low back pain-related disability, global perceived effect of improvement and pain self-efficacy (180th day follow-up). Conclusion: The results of this trial suggest the addition of PNE to SMT did not bring any additional effect on pain intensity and disability in the short term, but SMT + PNE can result in longer-lasting effects in patients with CLBP and that such an effect could be related to a possible mediator effect of pain self-efficacy.