Background: The Naples prognostic score (NPS) and its relation to the prognosis of oral squamous cell carcinoma (OSCC) have been inconclusive. This study aimed to investigate the correlation between NPS and the prognosis of postoperative OSCC patients. Additionally, the study sought to develop a new nomogram for predicting disease-free survival (DFS) and overall survival (OS). Methods: The study included 576 OSCC patients who underwent surgical treatment at two hospitals between August 2008 and June 2018. Univariate and multivariate Cox regression analyses were conducted to identify independent prognostic factors. Subsequently, two nomograms were developed to predict DFS and OS based on these factors and underwent rigorous validation. Results: The median DFS and OS were 31.5 months and 36.5 months, respectively. Significant differences in DFS and OS were observed among patients with different NPS scores. Adjuvant radiotherapy, age-adjusted Charlson comorbidity index (ACCI), extranodal extension (ENE), NPS, American Joint Committee on Cancer (AJCC) stage, surgical safety margin, eastern cooperative oncology group performance status (ECOG PS), and systemic inflammation score (SIS) were identified as independent predictors of DFS and OS. In the training cohort, the nomogram's concordance index (C-index) for predicting DFS and OS was 0.701 and 0.693, respectively. In the validation group, the corresponding values were 0.642 and 0.635, respectively. Calibration plots confirmed a high level of agreement between the model's predictions and actual outcomes. Decision curve analysis (DCA) demonstrated the nomogram's good clinical utility. Additionally, patients in the low-risk group did not benefit from adjuvant radiotherapy, while those in the medium-risk and high-risk group could benefit from adjuvant radiotherapy. Conclusion: NPS significantly influences the prognosis of OSCC patients following surgery. The nomogram developed in this study holds significant clinical application potential. The low-risk subgroup of patients was not required to undergo postoperative radiotherapy.