Background <p>Prior studies on the relationship between high-density lipoprotein cholesterol (HDL-C) and depression have reported inconsistent results. Insulin resistance (IR) can alter the composition and function of HDL. This study aims to investigate whether IR influences the association between HDL-C and depression.</p> Methods <p>Data from the National Health and Nutrition Examination Survey (2005–2018) were analyzed. Depression was assessed using the Patient Health Questionnaire-9, with a score of ≥ 10 indicating depression. IR was defined by a HOMA2-IR value of ≥ 2.5. Survey-weighted generalized linear models (GLMs) were used to examine the associations between HDL-C, IR, and depression. Multiplicative and additive interaction, along with subgroup analyses, evaluated HDL-C/IR interactions affecting depression. Sensitivity analyses were conducted by: (1) redefining IR, (2) adjusting for total cholesterol and triglycerides in the base models, (3) applying alternative weighting, and (4) including special participants.</p> Results <p>The study included 7,779 participants. Survey-weighted GLMs revealed no significant association between HDL-C or IR and depression. However, HDL-C and IR had a significant synergistic effect on the odds of depression (multiplicative scale[<i>P</i> &lt; 0.05] and additive interactions [relative excess risk due to interaction = 3.21]). Subgroup analyses confirmed IR significantly modified HDL-C-depression associations (<i>P</i>_interaction = 0.024). Specifically, in IR-positive individuals, Higher HDL-C linked to increased depression odds (odds ratio = 4.66, 95% confidence interval: 1.23–17.59, <i>P</i> = 0.02).</p> Conclusion <p>Elevated HDL-C in the context of IR were associated with increased depression odds. These findings underscore the importance of considering IR when examining the relationship between HDL-C and neuropsychiatric disorders.</p>