Objective To explore the impact of insulin resistance (IR) on the occurrence of post-stroke depression (PSD) and its predictive value. Methods A total of 242 patients with acute stroke admitted to Department of Neurology of Affiliated Tangshan Worker′s Hospital from October 2021 to September 2022 were subjected in this study. Then according to Hamilton Depression Scale-17 (HAMD-17), they were divided into PSD group (n=69) and non-PSD group (n=173). A self-designed questionnaire was used to collect their clinical data. National Institutes of Health stroke scale (NHISS), Essen stroke risk score (ESRS), and daily ability assessment scale (Barthel index) were employed to evaluate the stroke status. Laboratory indicators, such as lipids, high-sensitivity C-reactive protein (hs-CRP), hemoisocysteine (Hcy), fasting blood glucose (FBG) and fasting insulin (Fins) were collected. After homeostasis model assessment-insulin resistance (HOMA-IR) was calculated, the patients were divided into low-IR group (n=182) and high-IR group (n=60) with HOMA-IR value of P₇₅. SPSS statistics 26.0 was used for data analysis. Depending on data type, student′s t test, Mann-Whitney U test or Chi-square test was performed for comparison between groups. Logistic regression analysis was applied to analyze the effect of IR on PSD. Receiver operating characteristic (ROC) curve was drawn to evaluate the predictive value of IR for PSD. Results Significantly higher body mass index, NHISS score, total cholesterol, hs-CRP, Hcy, Fins levels and HOMA-IR, and lower Barthel index were observed in the PSD group when compared with the non-PSD group. The patients of male, and history of hypertension and hyperlipidemia were prone to PSD (P<0.05). Multivariate logistic regression analysis showed that history of hyperlipidemia (OR=3.52, 95%CI 1.44-8.62; P<0.05), NHISS score (OR=1.12,95%CI 1.00-1.25; P<0.05), hs-CRP (OR=1.11, 95%CI 1.04-1.19; P<0.05), Hcy (OR=1.07,95%CI 1.03-1.10; P<0.05) and HOMA-IR (OR=8.84,95%CI 3.86-20.22; P<0.05) were risk factors for PSD. The ROC curve showed that after introduction of HOMA-IR, ROC area under the curve was 0.88 (95%CI 0.84-0.92), sensitivity was 81.2%, and specificity was 78.8% (P<0.001). Conclusion IR is an independent risk factor for PSD. High HOMA-IR level at admission is associated with an increased risk of PSD.