Background Studies have shown that individuals with diabetes are more likely to suffer from depression, and metabolic dysregulation may be the pathophysiological mechanism underlying this comorbidity. The Cardiometabolic Index (CMI) is an innovative metric that integrates abdominal obesity and lipid levels, providing a comprehensive assessment of cardiometabolic health. Currently, the relationship between CMI and depression in diabetes has not been clarified. This study aims to explore the association between CMI and depression among American adults with diabetes. Methods This study enrolled 3,182 patients with diabetes from the National Health and Nutrition Examination Survey (2005-2018). A multivariable logistic regression model, restricted cubic spline (RCS) regression analysis, subgroup analysis, and interaction tests were employed to explore the association between CMI and depression. Mediation analysis was also performed to investigate the role of inflammatory factors-including neutrophils, lymphocytes, White Blood Cells, neutrophil-to-lymphocyte ratio (NLR), and systemic immune inflammation index (SII)-in the association between CMI and depression in patients with diabetes. Results We found that CMI is positively associated with depression in diabetes patients, and RCS regression analysis further confirmed a non-linear (L-shaped) relationship between CMI and depression, with an inflection point at CMI = 1.694. Depression risk increased significantly below this threshold but plateaued beyond it, suggesting a threshold effect primarily within the moderate to high CMI range. Subgroup analysis and interaction tests indicated that the association between CMI and depression was consistently present across all subgroups, with no significant differences observed among them (all interaction p-values > 0.05). Female, lower educational, lower household income, unmarried, smokers, and those with hypertension were more likely to develop depression among diabetes patients. Mediation analysis suggested that neutrophils and NLR significantly mediated the CMI-depression relationship, explaining 5.04% and 4.74% of the total effect, respectively. Conclusions In patients with diabetes, a non-linear (L-shaped) relationship exists between CMI and depression, and inflammatory factors significantly mediate this relationship.