Background: To investigate the expression, function, and related mechanisms of circHIPK3 in oral squamous cell carcinoma (OSCC). Methods: CircHIPK3 expression was determined by quantitative reverse transcription polymerized chain reaction (QRT-PCR) in OSCC and adjacent tissues, and the correlation between the circHIPK3 level and clinicopathological indexes of OSCC was analyzed. CircHIPK3 expressions in different OSCC cell lines were detected, cell counting kit-8 (CCK-8) and 5-bromodeoxyuridine (BrdU) assays were utilized to monitor cell proliferation and activity. Flow cytometry was adopted to detect apoptosis and transwell assay was used to detect cell invasion. The expressions of nuclear protein 1 (NUPR1), phosphatidylinositol 3 kinase (PI3K)/ protein kinase B (AKT) (PI3K/AKT) pathway proteins, and E-cadherin, Vimentin, and N-cadherin markers of epithelial-mesenchymal transformation (EMT) were detected by Western blot or Quantitative Real-time PCR (QRT-PCR).Results: Upregulated circHIPK3 was noted in OSCC tissues (compared with adjacent tissues), and its overexpression was related to OSCC size and histopathological grade. Functionally, overexpressed circHIPK3 can significantly promote EMT, proliferation, and invasion of OSCC cells and can inhibit cell apoptosis in vivo and in vitro. In addition, CircHIPK3 upregulated the activation of NUPR1 and PI3K/AKT. Bioinformatics analyses showed that miR-637 was the common target of circHIPK3 and NUPR1, while a dual luciferase reporting assay and RIP assay further demonstrated that circHIPK3 targeted miR-637 and bound to 3' UTR of NUPR1.Conclusions: CircHIPK3 demonstrates potential as a prognostic marker of OSCC and mediates OSCC progression via the miR-637-mediated NUPR1/PI3K/AKT axis.