Objective: To determine the effectiveness of a therapeutic patient education (TPE) intervention based on a biobehavioral approach combined with manual therapy (MT) to reduce pain in patients with chronic nonspecific neck pain (CNSNP). In addition, this study intended to assess the effectiveness of a multimodal physiotherapy program including TPE to reduce pain in patients with CNSNP. Design: Single-blind randomized controlled trial. Interventions: A total of 47 patients with CNSNP were randomized into three groups: (1) MT (control group); (2) MT plus TPE based on a biobehavioral approach (Exp1); and (3) MT plus TPE based on a biobehavioral approach, and therapeutic exercise (Exp2). Main Outcome Measurements: The clinical outcomes were recorded at baseline and at 1 and 4 months after the initiation of treatment. The primary outcome was pain intensity (Visual Analog Scale), and the secondary outcomes were pain catastrophizing (Pain Catastrophizing Scale), illness severity and global improvement (Clinical Global Impression Scale), and mechanosensitivity of the median nerve (Upper Limb Neural Test) and the cervical region (Modified Passive Neck Flexion Test). Results: Statistically significant differences in pain intensity were found when Exp2 was compared with Exp1 and the control group at 4 months (p = 0.015 and p = 0.001, respectively), but no difference was found between Exp1 and the control group at the same follow-up period (p = 0.86). Exp2 showed statistically significant differences in all of the secondary outcomes except for pain catastrophizing when compared with the control group at 4 months. Conclusions: The Exp2 group was more effective than Exp1 and the control group in terms of reducing pain intensity at 4 months; at post-treatment, only Exp2 was more effective than the control group.