BACKGROUND: Chronic pain and depression represent two global health problems with considerable economic consequences. Although existing literature reports on the relation between depression and pain conditions, meta-analytic evidence backing the mediating role of sleep disturbance as one of the main symptoms of depression is scarce. To examine the extent to which sleep disturbance mediates the depression-chronic pain association, we conducted a systematic review and meta-analysis of the associations of chronic pain, depression, and sleep quality. METHODS: We systematically searched for literature in MEDLINE and other relevant databases and identified cohort and case-control studies on depression, sleep disturbance, and chronic pain. Forty-nine studies were eligible, with a total population of 120 489 individuals. We obtained direct and indirect path coefficients via two-stage meta-analytic structural equation modelling, examined heterogeneity via subgroup analyses, and evaluated primary studies quality. RESULTS: We found a significant, partial mediation effect of sleep disturbance on the relation between depression and chronic pain. The pooled path coefficient (coef.) of the indirect effect was 0.03 (95% confidence interval [CI]: 0.01-0.05) and accounted for 12.5% of the total effect of depression on chronic pain. This indirect effect also existed for cohort studies (coef. 0.02; 95% CI: 0.002-0.04), European studies (coef. 0.03; 95% CI: 0.004-0.05), and studies that adjusted for confounders (coef. 0.04; 95% CI: 0.01-0.09). CONCLUSIONS: Sleep disturbance partially mediates the association between depression and pain. Although plausible mechanisms could explain this mediation effect, other explanations, including reverse causation, must be further explored. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42022338201.