Available evidence favors the use of pain neuroscience education (PNE) in patients with chronic pain. However, PNE trials are often limited to small sample sizes and, despite the current digital era, the effects of blended-learning PNE (ie, the combination of online digital media with traditional educational methods) have not yet been investigated.The study objective was to examine whether blended-learning PNE is able to improve disability, catastrophizing, kinesiophobia, and illness perceptions.This study was a 2-center, triple-blind randomized controlled trial (participants, statistician, and outcome assessor were masked).The study took place at university hospitals in Ghent and Brussels, Belgium.Participants were 120 people with nonspecific chronic spinal pain (ie, chronic neck pain and low back pain).The intervention was 3 sessions of PNE or biomedically focused back/neck school education (addressing spinal anatomy and physiology).Measurements were self-report questionnaires (Pain Disability Index, Pain Catastrophizing Scale, Tampa Scale for Kinesiophobia, Illness Perception Questionnaire, and Pain Vigilance and Awareness Questionnaire).None of the treatment groups showed a significant change in the perceived disability (Pain Disability Index) due to pain (mean group difference posteducation: 1.84; 95% CI = -2.80 to 6.47). Significant interaction effects were seen for kinesiophobia and several subscales of the Illness Perception Questionnaire, including negative consequences, cyclical time line, and acute/chronic time line. In-depth analysis revealed that only in the PNE group were these outcomes significantly improved (9% to 17% improvement; 0.37 ≤ Cohen d ≥ 0.86).Effect sizes are small to moderate, which might raise the concern of limited clinical utility; however, changes in kinesiophobia exceed the minimal detectable difference. PNE should not be used as the sole treatment modality but should be combined with other treatment strategies.Blended-learning PNE was able to improve kinesiophobia and illness perceptions in participants with chronic spinal pain. As effect sizes remained small to medium, PNE should not be used as a sole treatment but rather should be used as a key element within a comprehensive active rehabilitation program. Future studies should compare the effects of blended-learning PNE with offline PNE and should consider cost-effectiveness.