Herein, the function and potential molecular mechanisms of CRNDE and miR-384 were illustrated in glioma cells. CRNDE overexpression facilitated cell proliferation, migration, and invasion, while inhibited glioma cells apoptosis. Quantitative real-time polymerase chain reaction (PCR) demonstrated that miR-384 was downregulated in human glioma tissues and glioma cell lines. Moreover, restoration of miR-384 exerted tumor-suppressive functions. In addition, the expression of miR-384 was negatively correlated with CRNDE expression. A binding region between CRNDE and miR-384 was confirmed using luciferase assays. Moreover, CRNDE promoted cell malignant behavior by decreasing miR-384 expression. At the molecular level, treatment by CRNDE knockdown or miR-384 overexpression resulted in a decrease of piwi-like RNA-mediated gene silencing 4 (PIWIL4) protein. Besides, PIWIL4 was identified as a target of miR-384 and plays an oncogenic role in glioma. Similarly, downstream proteins of PIWIL4 such as STAT3, cyclin D1, VEGFA, SLUG, MMP-9, caspase 3, Bcl-2, and bcl-xL were modulated when treated with miR-384 and PIWIL4. Remarkably, CRNDE knockdown combined with miR-384 overexpression led to tumor regression in vivo.