Cutaneous squamous-cell carcinoma (cSCC) is the second most common skin cancer, with an increasing incidence in recent years. To define the molecular basis that drive cSCC development and progression, this study aimed at identifying potential novel molecular targets for the diagnosis and therapy of patients with cSCC. Two data sets with the accession number GSE45164 and GSE66359 were downloaded from Gene Expression Omnibus (GEO) database. After the identification of differentially expressed genes (DEGs) from these two data sets, respectively, between cSCC samples and controls, a combination of DEGs from these two data sets were subjected to the following analyses, including functional annotation, protein-protein interaction (PPI) network and module construction, transcription factor (TF)-target regulation prediction, and drug-gene interaction predictive analysis. A total of 204 upregulated genes and 213 downregulated genes were found in two data sets which were used for the follow-up analysis. Upregulated and downregulated genes were mainly involved in the functions such as cell division, mitotic nuclear division, cell cycle, and p53 signaling pathway. Interferon induced protein family members and proteasome subunit members were involved in the TF-target regulatory network, such as PSMB8, CXCL10, and IFIT3. Eight upregulated genes ( TOP2A, CXCL8, RRM2, PSMB8, PSMB9, PBK, CXCL10, and ISG15) that were hub genes in the PPI network and significant modules were identified in the predicted drug-gene interaction. In conclusion, TOP2A, CXCL8, RRM2, PSMB8, PSMB9, PBK, CXCL10, and ISG15 may be potential targets for the diagnosis and therapy of patients with cSCC.