Background <p>Gut microbiota dysbiosis plays a critical role in the pathogenesis of post-stroke depression (PSD). The role of microbiota-targeted dietary patterns in PSD remains uncharacterized. This population-based study evaluated the Dietary Index for Gut Microbiota (DI–GM) and PSD prevalence relationship in U.S. adults.</p> Methods <p>This cross-sectional study analyzed data from seven consecutive cycles (2005–2018) of the National Health and Nutrition Examination Survey (NHANES). Multivariable logistic regression assessed DI–GM–PSD associations, with restricted cubic splines (RCS) evaluating nonlinear trends. Stratified analyses assessed effect modification by demographic/clinical characteristics. Mediation analysis quantified the indirect effects of DI–GM on PSD through the mediator, body mass index (BMI).</p> Results <p>Adjusted analyses showed a negative association between DI–GM scores and PSD, with higher scores concurrently linked to lower PSD prevalence. The DI–GM scores ranged from 0 to 14. In Q4 DI–GM (7–14), PSD risk was 60% lower vs. Q1 (0–4) (OR = 0.40, 95% CI 0.23–0.71, <i>p</i> = 0.002). RCS regression depicted a curvilinear pattern between DI–GM scores and PSD risk (nonlinearity <i>p</i> = 0.015). Stratified analyses showed that higher DI–GM scores were associated with significantly lower rates of PSD in females (OR = 0.83, 95% CI 0.74–0.94; <i>p</i>-interaction = 0.026), but not in males. Mediation analysis suggested BMI partially mediated the association between DI–GM and PSD risk (proportion mediated: 19.2%, <i>p</i> = 0.018).</p> Conclusions <p>This study identified a negative association between DI–GM scores and the prevalence of PSD. Our findings suggest that dietary patterns beneficial to gut microbiota are associated with lower rates of PSD, and that this relationship is inter-related with BMI. These results highlight the potential clinical relevance of integrated dietary and weight management strategies, though longitudinal studies are needed to confirm any causal pathways.</p>