Abstract Background Colorectal cancer (CRC) is the leading cause for cancer mortality across the world. GRPEL2 is a critical regulator of mitochondria’s function with an oncogenic role in different kinds of cancer. The exact function of GRPEL2 -driven mitochondrial regulation and CRC progression have not been elucidated. Methods RNA-seq data from TCGA database was analyzed to identify biomarkers and therapeutic targets of CRC. The gene expression profile was validated by quantitative real-time PCR on 68 paired tumor and non-tumor samples from CRC patients. Tumorigenesis regulated by GRPEL2 was tested through EdU staining, Transwell assay, in vivo tumor growth and in vivo metastasis. The function of Mitochondria mediated by GRPEL2 was evaluated by transmission electron microscopy, DCFH-DA staining, mitochondrial membrane potential detection, and Calcein staining. LC–MS/MS screening and Co-IP were performed to discover protein partners of GRPEL2. E2F8-mediated transcriptional regulation of GRPEL2 was verified via Luciferase reporter and ChIP assays. Results GRPEL2 was upregulated in CRC tumor tissues and cell lines. High expression of GRPEL2 was associated with poor prognosis of CRC and inhibition of GRPEL2 suppressed CRC proliferation and migration by inducing mitochondria injury. Meanwhile, TIGAR was shown to interact with GRPEL2 and overexpression of TIGAR rescued CRC progression in the presence of GRPEL2 inhibition. Moreover, E2F8 was the upstream regulator of GRPEL2, which positively induced GRPEL2 transcription and expression in CRC. Conclusion Our work illustrated the oncogenic role of GRPEL2 in CRC development and determined the molecular mechanism of E2F8/GRPEL2/TIGAR pathway. These findings will provide novel insights and promising therapeutic targets for CRC treatment in the future.