AbstractBackgroundSquamous cell carcinoma (SCC) is a relatively common and heterogenous malignancy of different organs, such as the skin, esophagus, and lungs. Although most cases experience good survival with surgical methods, management of advanced types of the disease remains challenging. Several modalities, including different chemotherapy regimens and immunotherapies, have been investigated in this matter, among which Monoclonal antibodies (Mabs) are one of the most promising ones. Since the development of Mabs, they have been widely used to treat different diseases. Mabs have shown significant efficacy with high specificity along with acceptable safety, which makes them a favorable option in cancer therapy. In this article, we aimed to review the different aspects of using Mabs in SCC therapy.Recent FindingsWe found that treating with different Mabs has shown excellent efficacy accompanied by acceptable safety in treating SCC of different organs. Therefore, Mabs are considered great options in the treatment of SCC, especially in advanced cases. Overall, two highly potent types of Mabs in SCC therapy are anti‐EGFR Mabs and checkpoint inhibitors, especially Cetuximab, Nimotuzumab, and PD‐1 inhibitors. Bevacizumab is also a promising option as adjuvant therapy to other modalities.ConclusionAlthough some Mabs have shown promising outcomes in SCC therapy, their application as a part of cancer treatment depends on further investigations regarding cost‐effectiveness and predictors of response. FDA has approved several Mabs in SCC therapies, and Mabs may have a crucial role in this era in the near future, especially in treating head and neck and esophageal SCC and metastatic lung cancer.