To investigate the mediating effect of blood inflammatory markers on the relationship between obesity and depression in individuals with ischemic stroke. Methods: A total of 317 patients with ischemic stroke were assessed using the General Information Survey method and the Hamilton Depression Scale Descriptive analysis, correlation analysis, and mediation analysis were performed using SPSS 25.0 and statistical software R package 4.2.2. The significance of the mediation effect was tested using the percentile Bootstrap method. Results: After adjusted for age, gender, education levels, smoking status, alcohol consumption, hypertension, diabetes, coronary heart disease, hyperlipidemia, use of antidepressants, use of anti-inflammatory drugs, TOAST classification, NIHSS score, obesity and higher body mass index were found to be positively correlated with increased white blood cell count (WBC) and lymphocyte count (LYM) (WBC: β=0.76, P=0.044; β =0.06, P=0.002; LYM: β =0.37, P=0.008; β =0.03, P<0.001). Furthermore, there was a positive correlation between obesity and depressive symptoms (WBC: OR=3.47, P=0.017; LYM: OR=1.10, P=0.001). After including the mediating variable of blood inflammatory markers, the direct effect of obesity on depressive symptoms remained statistically significant. Additionally, when controlling for obesity indicators, a positive correlation between blood inflammatory markers and depressive symptoms was observed (WBC: OR=1.23, P=0.019; LYM: OR=1.62, P=0.027; NAR: OR=3.36, P=0.034). Analysis of the mediating effect indicated that the association between body mass index and depression was partially mediated by WBC and LYM, with the proportion of mediating effect being 9.77% and 13.95%, respectively. Conclusion: Blood inflammatory markers such as WBC and LYM exhibit a partial mediating effect in the relationship between obesity and depression.