Objectives <p>Inflammation and metabolic dysregulation are increasingly considered as key contributors to depression. However, the role of inflammatory-metabolic status in the association between diet quality and depression remains unclear. This study aimed to investigate whether inflammatory-metabolic status, as reflected by the monocyte-to-high-density lipoprotein cholesterol ratio (MHR), modifies the association between dietary patterns and depression, with a focus on potential sex-specific differences.</p> Methods <p>Adults participating in the US National Health and Nutrition Examination Survey (NHANES) 2005–2018 were included. Diet quality was evaluated using four dietary indices: the Healthy Eating Index-2020 (HEI-2020), Dietary Inflammatory Index (DII), Alternative Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH). Depressive symptoms were evaluated using the nine-item Patient Health Questionnaire (PHQ-9). Weighted multivariable logistic regression and restricted cubic spline (RCS) models were used to examine independent and joint associations between dietary patterns, MHR, and depression. Interaction effects between dietary patterns and MHR were assessed on both multiplicative and additive scales. Stratified analyses were conducted to examine the robustness of the results across subgroups.</p> Results <p>A total of 26,289 participants were included. A positive association between MHR and depression was found in women (OR = 1.61, 95% CI: 1.14–2.28), but not in men. Healthier dietary patterns, reflected by higher HEI-2020 and aMED scores, and lower DII scores, were associated with significantly lower odds of depression in both sexes. RCS analyses indicated a dose-response relationship between dietary pattern scores (HEI-2020, aMED, and DII) and depression. Joint analyses showed that women with both low MHR and high diet quality had the lowest odds of depression. The adjusted ORs were 0.54 (95% CI: 0.42–0.68) for HEI-2020, 0.33 (95% CI: 0.24–0.47) for DII, and 0.55 (95% CI: 0.42–0.71) for aMED. Notably, among women with low MHR, healthier dietary patterns were strongly associated with lower depression odds (HEI-2020: OR = 0.59, 95% CI: 0.44–0.79; DII: OR = 0.38, 95% CI: 0.26–0.55; aMED: OR = 0.62, 95% CI: 0.46–0.84), whereas these associations were weaker among those with high MHR (HEI-2020: OR = 0.75, 95% CI: 0.60–0.95; DII: OR = 0.79, 95% CI: 0.56–1.12; aMED: OR = 0.81, 95% CI: 0.62–1.06). A significant interaction between the DII and MHR on depression was observed in females (multiplicative interaction OR = 0.44, 95% CI: 0.25–0.75). Conversely, among men, the associations between dietary patterns and depression appeared largely independent of MHR status.</p> Conclusions <p>The associations between dietary patterns and depression differed across MHR levels in a sex-specific manner. A significant interaction between DII and MHR suggests that inflammatory-metabolic status may be involved in the diet - depression association.</p>