Background: This study aimed to evaluate the significance of the systemic immune-inflammation index (SII) and age in patients with vulvar squamous cell carcinoma (VSCC). Methods: We conducted a retrospective analysis of 79 VSCC patients treated at a tertiary cancer center between 1998–2021. SII was calculated as (neutrophil × platelet)/lymphocyte count. Optimal cutoff values were determined by receiver operating characteristic (ROC) curve analysis. Survival outcomes were analyzed using Kaplan-Meier and Cox regression methods. Results: Patients with high SII (≥497.975) had significantly higher rates of lymph node metastasis (p = 0.036, independent t-test with Welch’s correction). Age >65 years was associated with worse 5-year overall survival (OS) (70.7% vs. 83.5%, p = 0.003) and increased nodal involvement (p = 0.02). Multivariate analysis identified age >70 years (hazard ratio (HR) = 2.41, 95% confidence interval (CI): 1.32–4.39) and advanced International Federation of Gynecology and Obstetrics (FIGO) stage (HR = 3.02, 95% CI: 1.85–4.93) as independent prognostic factors. Conclusions: SII shows promise as a predictor of nodal metastasis in VSCC, while advanced age significantly impacts survival outcomes. These findings may help guide risk stratification and treatment decisions for this rare malignancy.