Background <p>The aim of the present study was to investigate the expression of tubulin-tyrosine ligase-like protein 12 (TTLL12) in oral squamous cell carcinoma (OSCC) and to explore its potential associations with clinicopathological characteristics and patient prognosis.</p> Methods <p>A total of 162 OSCC tissue samples and 30 adjacent normal tissue samples were collected from patients who underwent surgical resection at the First Affiliated Hospital of Chongqing Medical University between May 2014 and December 2018. Paraffin sections were prepared, and TTLL12 expression was detected via immunohistochemistry (IHC). The data were analyzed using SPSS 24.0 software.</p> Results <p>Immunohistochemical analysis revealed that TTLL12 expression was significantly higher in OSCC tissues than in normal controls. High TTLL12 expression was significantly correlated with increased tumor size, advanced clinical stage, cervical lymph node metastasis, and risk of new distant metastasis during the follow-up period (<i>P</i> &lt; 0.05). Multivariate Cox regression analysis revealed that TTLL12 expression was an independent prognostic factor for OSCC patient survival (<i>P</i> = 0.035). Moreover, patients with high TTLL12 expression had significantly shorter overall survival (OS) times than those with low TTLL12 expression (<i>P</i> &lt; 0.001).</p> Conclusions <p>Elevated TTLL12 expression is associated with enhanced tumor growth and metastasis in OSCC, leading to poor prognosis. These findings suggest that TTLL12 is a potential biomarker for prognostic assessment in patients with OSCC.</p>