Background This study aims to evaluate serum cytokine levels in individuals with primary Restless Legs Syndrome (RLS) and analyze their correlation with RLS symptom severity, sleep disturbances, anxiety, and depression. Methods A case-control study was conducted involving 87 primary RLS patients and 100 healthy individuals undergoing health check-ups. Serum cytokine levels were assessed, and RLS severity was evaluated using the International Restless Legs Syndrome Study Group (IRLSSG) rating scale. Additionally, the Pittsburgh Sleep Quality Index (PSQI), 24-item Hamilton Depression Rating Scale (HAMD24), and 14-item Hamilton Anxiety Rating Scale (HAMA14) were utilized to assess symptom severity, sleep disturbances, and emotional states in RLS patients. Results Serum cytokine levels, including IL-6 and TNF-alpha, were significantly higher in RLS patients compared to controls (P < 0.05). Adjustment for disease duration, sex, age, BMI, SBP, and DBP revealed an independent association between serum IL-6 and RLS (OR = 1.46; 95% CI = 1.02-1.93; P = 0.003). Linear regression analysis demonstrated a significant correlation between IL-6 levels and IRLS scores (beta = 0.123, P = 0.008). Conclusion Elevated circulating levels of inflammatory cytokines in RLS patients suggest a potential role of inflammation in the pathogenesis of primary RLS. Additionally, serum cytokine levels correlate closely with disease severity.