Purpose <p>Accumulating evidence indicates an association between major depression (MD) and the occurrence of low back pain/sciatica (LBP/S). In order to examine this association, we conducted a Mendelian randomization (MR) study, further evaluating the extent to which the length of mobile phone use mediates the impact of MD on the risk of developing LBP/S.</p> Methods <p>Genetic instruments and association estimates for MD, LBP/S, and length of mobile phone use were extracted from existing Genome-wide Association Study (GWAS) summary data. Bidirectional two-sample MR analyses were conducted to investigate the influence of MD on the risk of LBP/S. Furthermore, MR mediation analyses were executed to evaluate whether the length of mobile phone use mediates any effect of MD on LBP/S.</p> Results <p>MR analyses showed that a higher genetic risk for MD increased the odds of LBP/S (odds ratio [OR] 1.241; 95% confidence interval [CI], 1.065–1.446). The mediation analysis, employing a two-step MR approach, indicated that the observed effect was partially mediated by the length of mobile phone use, accounting for a mediated proportion of 12.0% (95% CI, 2.3–25.0%).</p> Conclusion <p>These findings may serve as a foundation for devising preventive strategies and interventions aimed at regulating the length of mobile phone use for individuals grappling with LBP/S in the context of MD.</p>