Background <p>This SONRIE randomized controlled trial (NCT05849792) examined the effects of a 12-week combined physical exercise and internet-based cognitive-behavioral therapy (iCBT) intervention on endocannabinoid system (ES) biomarkers and physical fitness in adults with mild-to-moderate depression.</p> Methods <p>Eighty adults were randomly assigned 1:1 to an intervention (IG) or control (CG) group. Outcomes included nine ES biomarkers (2-arachidonoylglycerol, 2-AG; anandamide, AEA; seven analogues) and physical fitness, including cardiorespiratory fitness (CRF; 6-minute walking test) and muscular strength. Measurements were taken at baseline, post-intervention and 8-week follow-up. Primary analysis performed 2 × 3 repeated-measures ANOVA on completers; mixed-effects intention-to-treat model as sensitivity analysis.</p> Results <p>No significant time × group interaction was detected for any ES biomarker, including 2-AG (F(2,88) = 0.17, <i>p</i> = 0.844) and AEA (F(2,88) = 1.20, <i>p</i> = 0.306); both groups showed comparable within-group decreases in 2-AG, 2-LG and 2-OG. The intervention significantly improved CRF [between-group difference + 81.6&#xa0;m at 12 weeks (F(2,78) = 7.88, <i>p</i> = 0.001)], exceeding the established minimal clinically important difference. None of the exploratory muscular fitness outcomes reached statistical significance; the arm curl test showed a borderline non-significant interaction (F(2,78) = 2.83, <i>p</i> = 0.065).</p> Conclusion <p>A 12-week internet-based combined exercise and iCBT intervention significantly improved CRF in adults with mild-to-moderate depression. We did not find evidence of an intervention-specific effect on plasma ES biomarkers. These findings support the inclusion of internet-delivered exercise and psychological interventions in comprehensive treatment strategies for depression.</p> Trial registration <p>ClinicalTrials.gov NCT05849792 (registered 6 May 2023).</p>