<p>Longitudinal studies have shown an association between diet quality and depression. However, reverse causality, unmeasured confounding, and selection bias remained important limitations. We aim to examine the relationship between diet quality and depression in older adults while addressing these issues and explore modification role of genetic predisposition to depression and low-grade inflammation. We emulated a target trial of dietary interventions using data from the ASPREE cohort. An ultra-processed food (UPF) index and an anti-inflammatory diet measure were extracted from a food frequency questionnaire to quantify diet quality. Depressive symptoms were assessed annually with a Center for Epidemiologic Studies-Depression 10-item score of ≥8. A polygenic score was derived using the latest Psychiatric Genomics Consortium data for major depression. Systemic inflammation was assessed using circulating high-sensitivity C-reactive protein. Inverse probability treatment weighting was applied to balance measured confounders. The effects of diet quality on depressive symptoms were estimated using generalised estimating equations. A total of 7220 participants (52.7% female), aged 70+ years, were followed for a median of 5.7 years. High UPF consumption was associated with a higher risk of depressive symptoms (RR: 1.12, 95% CI: 1.03–1.21), while an anti-inflammatory diet was associated with lower depressive symptoms (RR: 0.93, 95% CI:&#xa0;0.86–1.00). Genetic predisposition or low-grade inflammation did not modify the observed associations. Higher diet quality is associated with a lower risk of depressive symptoms, independent of genetic predisposition or low-grade inflammation, which may support dietary interventions as a modifiable lifestyle strategy for mental health promotion and prevention in older adults.</p>