Cutaneous squamous cell carcinoma (cSCC) often follows actinic keratosis (AK) and is the second most common skin cancer worldwide. To reduce metastasis risk, it is important to diagnose and treat cSCC early. This study aimed to identify hub genes associated with cSCC and AK.This study used three datasets GSE45216, GSE98774, and GSE108008. We combined samples from the GSE45216 and GSE98774 datasets into the new dataset GSE45216-98774. We applied a weighted gene co-expression network analysis (WGCNA) to investigate key modules and hub genes associated with cSCC and AK. We considered the hub genes found in both the GSE45216-98774 and GSE108008 datasets as validated hub genes. We tested whether the expression of hub genes could predict patient survival outcomes in other cancers using TCGA pan-cancer data.We identified modules most relevant to cSCC and AK. Additionally, we identified and validated seven hub genes of cSCC: GATM, ARHGEF26, PTHLH, MMP1, POU2F3, MMP10 and GATA3. We did not find validated hub genes for AK. Each hub gene was significantly associated with the survival of various cancer types. Only GATA3 was significantly associated with melanoma survival.We applied WGCNA to find seven hub genes that play important roles in cSCC tumorigenesis. These results provide new insights that help explain the pathogenesis of cSCC. These hub genes may become biomarkers or therapeutic targets for accurate diagnosis and treatment of cSCC in the future.© 2021. The Author(s).