Background: Inflammation within tumor microenvironments has been correlated to numerous malignancies. This study aims to explore its significance in thyroid cancer (TC). Methods: Retrospective analysis of 157 thyroid carcinomas and 40 benign cases involved initial univariate analysis. The value of neutrophils/value of lymphocytes (NLR), value of platelets/value of lymphocytes (PLR), value of lymphocytes/value of monocytes (LMR), and value of platelets × value of neutrophils/value of lymphocytes (SII) indexes were related to TC characteristics and number and location of involved lymph nodes using χ² or Fischer’s exact tests for categorical variables and Student’s t-tests for continuous ones. A 1:1 propensity score matching balanced malignant and benign TC groups based on age, sex, and tumor size was used. Post-matching, a multivariate logistic model integrated sex, age, Central lymph node metastases (CLNM), and SII index. Statistically significant immune index values underwent ROC curve analysis for determining cut-offs. Among the 157 malignant TC, median test and density plots were performed. Results: The SII index emerged as a predictor of malignancy in both univariate and multivariate analyses (p-value = 0.0202). The ROC curve indicated a cut-off SII value of 465.71, (specificity = 58% [95% CI: 0.43–0.73]; sensitivity = 80% [95% CI: 0.68–0.93]). Median SII index values for tumor sizes of 1 and >1 were 522.8 and 654.8, respectively (p-value = 0.016). When central lymph nodes metastases(CLNMs) was considered (CLNM = 0 vs. CLNM > 0), median SII values were 530.7 and 1121.7, respectively (p-value = 0.011). Conclusions: The SII index appears to be a valuable tool in the presence of TC, showing correlations with malignancy, tumor size, and CLNMs.