Oral cavity squamous cell carcinoma (OCSCC) represents a serious health and socio-economic problem in different geographical areas of the world. It is characterized by a high rate of mortality, recurrence and metastasis. Despite the therapeutic strategies implemented for its management and resolution, currently the survival estimate for locally advanced disease is about 50%. The available therapeutic options comprise surgery and pharmacological treatment. Recently, an increased emphasis has been placed on the drugs that might be of benefit in this life-threatening disease. Therefore, the aim of this present review was to offer a general survey of the current available pharmacological treatment for OCSCC. The PubMed database was used to retrieve the papers using “OCSCC” as the search terms. We limited our search to the last 5 years to give a more updated and recent picture of the state of the art, including preclinical and clinical investigations. We found that 77 out of 201 papers were on the surgical treatment of OCSCC, 43 out of 201 focused on the radiotherapy and 81 out of 201 underwent evaluation for the aim of our review. We excluded the case reports, editorial letters, observational studies and papers written in languages other than English. A total of 12 articles were included in the final review. Our results showed that nanotechnologies use to enhance the efficacy of anticancer drugs such as: cisplatin, paclitaxel, cetuximab, EGFR antagonists, MEK1/2 and immune check inhibitors combination could have promising anti-cancer activity. However, the paucity of available data on drugs suggests the urgent need to improve the pharmacological armamentarium for OCSCC treatment.