Glioblastoma (GBM) is the most prevalent and aggressive form of central nervous system (CNS) tumors, with low patient survival rates despite recent treatment advancements. Traditional diagnosis relies on neuroimaging and postoperative histopathological and molecular analysis, but these methods struggle to differentiate tumor progression from treatment-related changes. Tissue biopsies are invasive and not suitable for monitoring ongoing treatments. Liquid biopsy, particularly through blood samples, offers a promising alternative for GBM diagnosis and monitoring. Blood and cerebrospinal fluid (CSF) sampling provide minimally invasive means to obtain tumor-related information. Various circulating biomarkers, including cell-free nucleic acids (ctDNA), microRNAs (miRNAs), circulating tumor cells (CTCs), proteins, extracellular vesicles (EVs), and metabolites, have been identified in biofluids and can cross the blood-brain barrier (BBB). These biomarkers offer real-time and dynamic monitoring of tumor characteristics and treatment responses. However, the clinical utility of liquid biopsy-based biomarkers is constrained by limitations such as lack of standardized methodologies, small cohort sizes, and the short half-life of some biomarkers. The objective of liquid biopsy should be to complement traditional methods by providing additional information, enhancing diagnostic accuracy and monitoring. Combining diverse biomarker types may improve clinical effectiveness. This review discusses the latest research on circulating biomarkers in GBM, their potential as diagnostic, predictive, and prognostic indicators, and associated challenges and future perspectives.Glioblastoma (GBM) is the most prevalent and aggressive form of central nervous system (CNS) tumors, with low patient survival rates despite recent treatment advancements. Traditional diagnosis relies on neuroimaging and postoperative histopathological and molecular analysis, but these methods struggle to differentiate tumor progression from treatment-related changes. Tissue biopsies are invasive and not suitable for monitoring ongoing treatments. Liquid biopsy, particularly through blood samples, offers a promising alternative for GBM diagnosis and monitoring. Blood and cerebrospinal fluid (CSF) sampling provide minimally invasive means to obtain tumor-related information. Various circulating biomarkers, including cell-free nucleic acids (ctDNA), microRNAs (miRNAs), circulating tumor cells (CTCs), proteins, extracellular vesicles (EVs), and metabolites, have been identified in biofluids and can cross the blood-brain barrier (BBB). These biomarkers offer real-time and dynamic monitoring of tumor characteristics and treatment responses. However, the clinical utility of liquid biopsy-based biomarkers is constrained by limitations such as lack of standardized methodologies, small cohort sizes, and the short half-life of some biomarkers. The objective of liquid biopsy should be to complement traditional methods by providing additional information, enhancing diagnostic accuracy and monitoring. Combining diverse biomarker types may improve clinical effectiveness. This review discusses the latest research on circulating biomarkers in GBM, their potential as diagnostic, predictive, and prognostic indicators, and associated challenges and future perspectives.