Glioma, the most frequent primary intracranial tumor, is characterized by infiltrative growth in the central nervous system, pronounced invasiveness, high malignancy, and poor clinical prognosis. The existing treatment methods include surgery, radiotherapy and chemotherapy, but the efficacy is still limited. Analysis of The Cancer Genome Atlas (TCGA) dataset reveals marked downregulation of acid-sensing ion channel 2 (ASIC2) expression in glioma tissues, which significantly correlates with reduced patient survival. Moreover, ASIC2 expression is inversely associated with the extent of immune cell infiltration and glioma stem cell markers. Functional experiments demonstrate that both knockdown and overexpression of ASIC2 critically regulate glioma cell proliferation, invasion, and metastatic potential through mechanisms mediated by matrix metalloproteinase 2 (MMP2), calcineurin, and nuclear factor of activated T cells 1 (NFAT1) signaling pathways. These findings delineate a pivotal role for ASIC2 in governing glioma malignant behavior and establish its relevance as a potential molecular target for therapeutic intervention.