Background: Glioblastoma (GBM) represents an aggressive malignancy in the central nervous system, with a poor prognosis. Despite ongoing research efforts, there is still a lack of effective treatments, leading to the need for new therapeutic targets. Collagen plays a crucial role in the extracellular matrix and can impact the progression of cancer. Yet the potential involvement of COL22A1 (Collagen Type XXII Alpha 1 chain) in GBM has not been investigated. Materials and Methods: The expression of COL22A1 was evaluated in both clinical GBM samples and the Gene Expression Profiling Interactive Analysis (GEPIA) database. Following COL22A1 knockdown in GBM cells, functional assays were conducted to assess proliferation, migration, and invasion. The influence of COL22A1 on oncogenic signaling pathways was analyzed through luciferase reporter assays and interventions with pharmacological agents. In vivo experiments were performed using a nude mouse xenograft model. Results: COL22A1 expression was significantly higher in GBM tissues and was linked with a poor prognosis. Silencing COL22A1 suppressed proliferation, migration, and invasion of GBM cells and impeded tumorigenesis in vivo. On a mechanistic level, COL22A1 impacted the PI3K/AKT signaling cascade, demonstrated by decreased FOXO transcriptional activity and lower levels of phosphorylated PI3K (p-PI3K) and phosphorylated AKT (p-AKT). Furthermore, stimulating the PI3K/AKT pathway partially mitigated the impact of COL22A1 silencing. Conclusion: COL22A1 plays a crucial role in dictating the malignancy of GBM through regulating the PI3K/AKT signaling pathway. Targeting COL22A1 could present a novel approach for GBM management.