Calcyclin-binding protein or siah-1-interacting protein (CACYBP/SIP), a target protein of calcyclin S100A6 and an essential component of E3 ubiquitin ligase, had been proven to play significant roles in some cancers, but its pan-cancer function remains unknown. In the present study, we used a series of databases, including TCGA, GTEx, CPTAC, HPA, cBioPortal, UCLCAN, UCSC, CancerSCEM, CancerSEA, CancerSEA, GEPIA2 and STRING to explore the potential roles of CACYBP in pan-cancer. We systematically revealed the expression patterns of CACYBP, and the potential associations between CACYB expression and genetic alternation, prognosis, DNA methylation, RNA modification, immune reactivity, tumor stemness and enrichment pathways in pan-cancer. The results showed that CACYBP was significantly increased in various cancers compared to corresponding normal tissues. CACYBP mutation was frequently presented in various cancers. In addition, CACYBP expression was significantly correlated with prognosis, DNA methylation, RNA methylation, immune cells infiltration, immune checkpoint genes (ICGs), immune scores, tumor mutational burden (TMB), microsatellite instability (MSI) and tumor stemness in various cancers. We also discovered that CACYBP was abundantly highly expressed in the majority of cancers at a single-cell level and was significantly positively correlated to the single-cell functions of certain tumors, such as the cell cycle, DNA damage and DNA repair. Furthermore, CACYBP-related genes were mainly enriched in signaling pathways correlated with the tumor microenvironment (TME) and cancer development. Taken together, CACYBP plays an essential role in oncogenesis, and might serve as a promising prognostic biomarker and immunotherapeutic target in human cancers.