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Introduction: Keratoacanthoma (KA) and squamous cell carcinoma (SCC) are two cutaneous conditions with morphological resemblance, which can complicate the diagnosis in some cases. Using immunohistochemistry staining of biomarkers could be beneficial in resolving this obstacle. Objectives: we investigated a variety of biomarkers assessed in different studies in order to find the most important and helpful biomarkers for differentiation between SCC and lesions capable of spontaneous regression. Methods: PubMed medical literature and Google Scholar database were used to identify relevant literature up to 15 June 2022. The aim of our analyses was to determine the capability of biomarkers to distinguish SCC from lesions capable of spontaneous regression using calculated individual and pooled OR and 95% CI and I2 tests. Results: Six potential biomarkers are CD10 with pooled OR= 0.006 (95% CI 0.001 to 0.057) and I2=0%; COX-2 with pooled OR=0.089 (95% CI 0.029 to 0.269) and I2=17.1%; Elastic Fibers with pooled OR= 6.69 (95% CI 2.928 to 15.281) and I2=0%; IMP-3 with pooled OR=0.145 (95% CI 0.021 to 1.001) and I2=44.5%; P53 with pooled OR=0.371 (95% CI 0.188 to 0.733) and I2=55.9%; AT1R with OR=0.026 (95% CI 0.006 to 0.107). Conclusions: We suggest the utilization of the following IHC biomarkers for discrimination between lesions with spontaneous regression such as KA and SCC: CD10, COX-2, and Elastic Fibers.