Background Oral squamous cell carcinoma (OSCC) accounts for the majority of oral cancers globally. It is characterized by metastasis, poor prognosis, high recurrence rate, and poor five-year survival rate due to late detection or diagnosis at an advanced stage. Novel biomarkers that can predict the prognosis of patients with OSCC are needed to improve survival. Lysosome-associated membrane protein-3 (LAMP3) glycoprotein, a member of the LAMP protein family, is a molecular marker for mature dendritic cells. LAMP3 expression has been correlated with unfavorable prognosis in patients with various cancers. Few studies have examined the relationship between LAMP3 and clinicopathological parameters in OSCC. This study aims to analyze the immunohistochemical expression of LAMP3 in OSCC and its relationship with clinicopathological characteristics. Methodology In this study, 75 formalin-fixed, paraffin-embedded samples of cases diagnosed with primary OSCC were obtained and immunostained with LAMP3 antibody. Its expression was compared with clinicopathological parameters such as age, sex, tobacco and alcohol consumption habits, differentiation, TNM staging, tumor location, lymph node metastasis, lymphovascular invasion, perineural invasion, and pattern of invasion. Results Higher LAMP3 expression was highly significantly associated with the TNM stage (p = 0.001). High expression of LAMP3 was significantly associated with T stage (p = 0.002) and lymph node metastasis (p = 0.002). All poorly differentiated OSCC cases (n = 2, 100%) showed a high expression of LAMP3. Conclusions High LAMP3 expression and its significant association with TNM stage, T stage, and lymph node metastasis suggest a potential role for LAMP3 in OSCC carcinogenesis. High LAMP3 expression in poorly differentiated OSCC might indicate that it plays a pivotal role in oncogenic cell transformation. Our results indicate that LAMP3 may be a predictive marker for poor prognosis in OSCC.