Objective: To assess the association between depression severity, measured using the Patient Health Questionnaire-9 (PHQ-9), and inflammatory markers (IL-6, TNF-α) in adult hemodialysis patients. Methodology: This cross-sectional study enrolled 100 adult patients undergoing maintenance hemodialysis thrice weekly for at least six months. Depression symptoms were evaluated using the PHQ 9 questionnaire. Fasting venous samples were collected pre-dialysis to measure serum IL-6 and TNF-α using ELISA kits. Patients were stratified into depression categories based on PHQ-9 scores. Correlations between PHQ-9 and inflammatory markers were analyzed using Spearman’s correlation and multiple linear regression. Results: The mean age of participants was 52.6 ± 12.4 years, and 58% were male. Based on PHQ-9, 32% had minimal depression, 28% mild, 22% moderate, and 18% severe depression. Mean serum IL-6 increased progressively across depression categories (6.8 ± 2.1 pg/mL in minimal vs. 12.4 ± 3.6 pg/mL in severe). Similarly, TNF-α levels were significantly higher in severe depression (18.3 ± 5.2 pg/mL) compared with minimal depression (9.7 ± 3.1 pg/mL). PHQ-9 scores showed significant positive correlations with IL-6 (r = 0.56, p < 0.001) and TNF-α (r = 0.49, p < 0.001). In adjusted regression models, IL-6 remained an independent predictor of higher PHQ-9 scores (β = 0.41, p = 0.002). Conclusion: Depression severity in hemodialysis patients is strongly associated with elevated IL-6 and TNF-α levels, supporting the role of inflammation in dialysis-related depression. Routine psychological screening and targeted anti inflammatory strategies may improve mental health outcomes in this population.