(1) Background: Chronic musculoskeletal pain (CMP) in adolescents can negatively affect physical, psychological, and social functioning, resulting in functional disability. This randomized controlled trial (RCT) aimed to evaluate the effectiveness of an outpatient rehabilitation program based on graded exposure in vivo (EP) compared with care as usual (CAU: interdisciplinary outpatient rehabilitation care). Both EP and CAU aim to improve functional ability in adolescents with CMP. (2) Methods: Pragmatic multicenter RCT with 12-month follow-up. Adolescents (12-21 years) with CMP were invited to participate. Primary outcome: functional disability; secondary outcomes: perceived harmfulness; pain catastrophizing; pain intensity. Data analysis: intention-to-treat linear mixed model. (3) Results: Sixty adolescents (mean 16 years) were randomized; data for 53 were analyzed. Adolescents in EP showed relevant and significant decreases in functional disability (estimated mean difference at least -8.81, ≤ 0.01) compared with CAU at all times. Significant differences in favor of EP were found for perceived harmfulness at all times ( ≤ 0.002), for pain catastrophizing at 2 months ( = 0.039) and for pain intensity at 4 and 10 months ( ≤ 0.028). (4) Conclusion: EP leads to a significant and clinically relevant decrease in functional disability compared with usual care.