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Simple Summary: Brain tumors, including glioblastoma (GB), pose a significant health concern globally, with high mortality rates despite current therapies. Pentraxin 3 (PTX3) is a multifunctional regulatory protein implicated from the early stages of inflammatory processes. Recent studies suggest PTX3's involvement in tumor progression, including metastasis and invasion, in multiple cancer types. However, the role of PTX3 in GB remains poorly understood. This review aims to discuss PTX3's function in GB pathology, considering its diverse biological activities and its potential as a promising molecular target. Understanding PTX3's role in GB could provide insights into novel therapeutic approaches to improve patient outcomes and survival rates. Brain tumors are a heterogeneous group of brain neoplasms that are highly prevalent in individuals of all ages worldwide. Within this pathological framework, the most prevalent and aggressive type of primary brain tumor is glioblastoma (GB), a subtype of glioma that falls within the IV-grade astrocytoma group. The death rate for patients with GB remains high, occurring within a few months after diagnosis, even with the gold-standard therapies now available, such as surgery, radiation, or a pharmaceutical approach with Temozolomide. For this reason, it is crucial to continue looking for cutting-edge therapeutic options to raise patients' survival chances. Pentraxin 3 (PTX3) is a multifunctional protein that has a variety of regulatory roles in inflammatory processes related to extracellular matrix (ECM). An increase in PTX3 blood levels is considered a trustworthy factor associated with the beginning of inflammation. Moreover, scientific evidence suggested that PTX3 is a sensitive and earlier inflammation-related marker compared to the short pentraxin C-reactive protein (CRP). In several tumoral subtypes, via regulating complement-dependent and macrophage-associated tumor-promoting inflammation, it has been demonstrated that PTX3 may function as a promoter of cancer metastasis, invasion, and stemness. Our review aims to deeply evaluate the function of PTX3 in the pathological context of GB, considering its pivotal biological activities and its possible role as a molecular target for future therapies. [ABSTRACT FROM AUTHOR]