BackgroundNeoplasms are a series of diseases affecting human health. Prognostic and tumor status–related markers for various tumors should be identified.MethodsBased on 19,515 samples from multiple sources, for the first time, this study provided an overview of gene S-phase kinase associated protein 2 (SKP2) in pan-cancer. DifferentialSKP2expression in multiple comparison groups was identified by the Kruskal–Wallis test and Wilcoxon rank-sum test. The prognosis significance ofSKP2in individuals with neoplasm was evaluated through univariate Cox regression analysis and Kaplan-Meier curves. The area under the curve was utilized to detect the accuracy ofSKP2in predicting cancer status. Spearman’s rank correlation coefficients were calculated in all correlation analyses. Gene set enrichment analysis was used to identify essential signaling pathways ofSKP2in human neoplasms.ResultsThe study disclosed the upregulatedSKP2expression in 15 neoplasms and decreasedSKP2expression in three cancers (p< 0.05). The transcription factor Forkhead Box M1 may contribute to the increased expression levels ofSKP2in certain tumors. Over-expressedSKP2represented a risk factor for the prognosis of most cancer patients (hazard ratio > 1,p< 0.05).SKP2expression made it feasible to distinguish neoplasm and control tissues of 21 neoplasms (sensitivity = 0.79, specificity = 0.87, area under the curve = 0.90), implying its potential in screening a series of neoplasms. Further, the research revealed the close association ofSKP2expression with DNA methyltransferases, mismatch repair genes, microsatellite instability, tumor mutational burden, neoantigen count, and immunity.ConclusionsSKP2plays an essential role in multiple neoplasms and may serve as a marker for treating and identifying these neoplasms.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12920-023-01561-4.