Background <p>Glioblastoma (GBM) relapse and drug resistance are driven by a subset of quiescent, therapy-tolerant cells that persist in the G0 phase. However, the molecular mechanism coupling immune signaling to tumor cell quiescence and metabolic adaptation remains unclear.</p> Methods <p>Multi-omics analyses of TCGA, CGGA, and GEO datasets, combined with single-cell transcriptomics and in vitro/in vivo experiments, were used to identify complement-related regulators of G0 maintenance. Genetic manipulation (shRNA/overexpression), pharmacological inhibition (C5AR1 antagonist JPE1375; STAT3 inhibitor Stattic), and rescue experiments with recombinant C3 were performed in glioma cell lines and xenograft models. Cell-cycle, mitochondrial, and redox states were assessed by flow cytometry, immunofluorescence, MitoTracker/MitoSOX staining, and ELISA.</p> Results <p>C5AR1 expression was markedly upregulated in GBM and correlated with poor prognosis (HR = 2.7, <i>p</i> = 6.4 × 10⁻¹⁴). Single-cell and functional analyses revealed that C5AR1, activated by complement C3, sustains a spontaneous G0 population through JAK2/STAT3/STAT5 signaling. This axis enhanced mitochondrial integrity and oxidative phosphorylation, maintained low ROS homeostasis, and preserved stem-like features conferring chemoresistance. Knockdown or pharmacological blockade of C5AR1 disrupted G0-phase maintenance, decreased mitochondrial activity, and suppressed tumor growth in xenografts. C5AR1 inhibition also sensitized glioma cells to metabolic drugs by reversing rosiglitazone resistance and enhancing metformin efficacy.</p> Conclusions <p>C5AR1 links extracellular complement activation to intracellular G0-phase maintenance and metabolic resilience in glioma. Targeting the C3-C5-C5AR1 axis disrupts quiescence-driven drug tolerance and represents a promising therapeutic strategy for overcoming chemoresistance in GBM.</p>