Orai1, which is involved in store-operated calcium entry, has recently been implicated in cancer progression. However, the role of Orai1 in colorectal cancer (CRC) progression remains unclear. We used real-time PCR and western blot to measure Orai1 expression in four CRC cell lines, 60 tumor pairs, and corresponding non-tumor tissues from CRC patients. Immunohistochemistry was performed to examine Orai1 expression in CRC and corresponding non-tumor tissues. Statistical analyses were applied to evaluate the prognostic value and associations of Orai1 expression with clinical parameters. Furthermore, the Orai1 gene was overexpressed in HCT116 cell and silenced with siRNA in LOVO cell. Moreover, cell proliferation and apoptosis were measured using MTT assay and flow cytometry, and a molecular mechanism of Orai1 regulation by miR-519 was explored. Orai1 expression was higher in CRC tissues than adjacent non-cancerous tissues, and this was positively correlated in CRC patients with distant metastasis and poor prognosis. Also, increased expression of Orai1 was observed in highly invasive CRC cell lines and ectopic expression of Orai1 enhanced cell proliferation and inhibited apoptosis; silencing Orai1 suppressed cell proliferation and induced apoptosis. The Akt/GSK3 beta pathway contributed to Orai1 effects in CRC cells, and Orai1 was a direct target of miR-519, a microRNA not previously reported to be involved in both CRC tissues and cell lines. We identified a novel CRC regulatory circuit involving the miR-519-Orai1 axis, and dysfunction of this drives diverse aspects of CRC pathogenesis.