Nuclear receptor subfamily 5 group A member 2 (NR5A2) is known to be a key regulator in the development of a variety of tumor types. However, it is still uncertain how NR5A2 affects cutaneous squamous cell carcinoma (cSCC). The aim of this work, therefore, was to determine the function of NR5A2 in cSCC proliferation, cell cycling, cell migration, and invasion. In this study, based on a systematic study of previous data, we conducted a preliminary exploration of NR5A2 expression in cSCC using bioinformatics databases. Immunohistochemical staining for NR5A2 expression was then performed in cSCC tissues and healthy tissues from 7 patients. NR5A2 expression was also examined in human keratin-forming cells (HaCaT) and human cSCC cell lines (A431, Colo-16, SCL-1, and SCL-2). A stable A431 cell line consisting of sh-RNA-NR5A2 was created to detect changes in cell proliferation, cell cycle, clonogenic ability, and the key proteins about the Wnt/β-catenin pathway. The results illustrated that NR5A2 showed enhanced expressed in cSCC tissues than in healthy adjacent tissues and was more robustly expression in Colo-16, A431, SCL-1, and SCL-2 cells versus HaCaT cells. Downregulation of NR5A2 expression in cSCC cells led to a less malignant phenotype. NR5A2 knockdown decreased the expression of proteins in the Wnt/β-catenin, and this inhibition could be reversed by the Wnt signaling pathway agonist LiCl. In conclusion, NR5A2 appears to encourage the development and metastasis of cSCC by Wnt/β-catenin pathway.