Long non-coding RNAs (lnRNAs) colorectal neoplasia differentially expressed (CRNDE) has been identified as a crucial regulator involved in tongue squamous cell carcinoma (TSCC). However, the molecular mechanism of CRNDE involved in TSCC progression is still unknown. In the study, qRT-PCR assay was used to detect the expression of CRNDE in TSCC tissues and cells. CCK-8 assay, colony formation assay, transwell assay and flow cytometric analysis were performed to determine cell proliferation ability, colony formation, migration and invasion capacities, and cell apoptosis, respectively. Western blot was employed to assess the activity of the PI3K/AKT/mTOR pathway. A xenograft mice model was performed to evaluate the role of CRNDE on tumor growth in vivo. The results showed CRNDE was upregulated in TSCC tissues and cell lines. CRNDE knockdown repressed the proliferation, colony formation, migration and invasion and promoted apoptosis in TSCC cells. Moreover, CRNDE regulated the PI3K/AKT/mTOR pathway in TSCC cells. Additionally, high levels of CRNDE inhibited tumor growth in vivo. In conclusion, high levels of CRNDE might promote TSCC progression at least partly through regulating the PI3K/AKT/mTOR pathway. Targeting CRNDE has potential to be used as a novel target of TSCC treatment.