Oral squamous cell carcinoma (OSCC) is one of the major leading cancers worldwide. Generally, the incidence of OSCC remains constant globally but appears increasing in some parts of the world especially in the young group. Despite an easy access to early diagnosis and treatment, the mortality rate of patients with OSCC remains high due to delayed treatment and failure to control tumor recurrences and metastasis. The overall five-year survival rate for OSCC is considerably lower than other cancers and has not significantly changed during the last two decades. Recently, novel treatments, aiming to target specific molecules, aberrantly expressed during OSCC carcinogenesis, have been investigated and tested in clinical trials at several research settings. COX-2, in particular, is significantly overexpressed in OSCC and suggested to play a crucial role in OSCC carcinogenesis. This review will focus on the association between OSCC and COX-2 and the use of the COX-2 inhibitors as the targeted therapy for OSCC. This new approach in OSCC treatment offers hope that it may replace the conventional treatment modalities considered nonspecific and causing unwanted severe complications to patients.