Background: Gliomas are the most common primary tumours of the central nervous system. Despite a multimodal therapeutic approach combining surgery, radiotherapy, and temozolomide (TMZ), treatment remains highly challenging, and the prognosis is poor. One of the potential molecular targets that may improve therapeutic outcomes is the purinergic receptor P2X7 (P2X7R). Methods: The aim of this systematic review was to summarize current knowledge on the expression, functionality, and therapeutic relevance of P2X7R in gliomas. A comprehensive literature search was conducted in three databases (PubMed, Scopus, and Web of Science) up to 12 April 2025. Original in vitro and in vivo studies evaluating P2X7R in glioma models were included. Results: A total of 41 studies met the inclusion criteria and were analyzed. For each included study, the risk of bias was assessed using the OHAT Risk of Bias Tool. The review protocol was registered in PROSPERO. Although individual studies differed in methodology and outcomes, the majority reported that P2X7R modulation affected glioma cell behaviour, including proliferation, survival, migration, immune signalling, and response to treatment. Due to the heterogeneity of models and endpoints, a narrative synthesis was performed. Conclusions: Overall, current evidence suggests that P2X7R may represent a biologically relevant and pharmacologically actionable target in gliomas, although further high-quality studies are required to confirm its clinical potential.