Background: Glioblastoma (GBM) is an aggressive brain malignancy with a poor prognosis. The metabolic syndrome, characterized by aberrant glucose and lipid metabolism, may influence GBM treatment outcomes. This study aimed to explore the impact of glucose and lipid metabolic parameters in patients with metabolic syndrome on the therapeutic response of GBM. Methods: A retrospective case-control study was conducted, involving 228 GBM patients with metabolic syndrome treated from January 2019 to January 2022. Patients were categorized into good and poor response groups based on survival beyond or below 15 months post-treatment. Demographic, clinical, and metabolic data were collected, including blood glucose, lipid profiles, and inflammatory markers. Univariate and multivariate logistic regression analyses identified predictors of treatment response. Results: Elevated glucose and lipid parameters were associated with poor treatment responses. Mean serum glucose, glycated hemoglobin (HbA1c), and homeostatic model assessment of insulin resistance (HOMA-IR) were higher in the poor response group (P = 0.01, P < 0.001, P = 0.022, respectively), correlating positively with poor outcomes in multivariate analysis. Dyslipidemia, characterized by high triglycerides (TG) and high-density lipoprotein cholesterol (HDL), and low low-density lipoprotein cholesterol (LDL) levels, significantly predicted poorer responses (TG P < 0.001; LDL P = 0.012; HDL P < 0.001). Elevated C-reactive protein (CRP), interleukin6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) levels were also linked to worse outcomes, indicating a role of systemic inflammation. Epidermal growth factor receptor (EGFR) amplification was more common in poor responders, while O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was linked to better outcomes (P = 0.002 and P = 0.001, respectively). Conclusion: Dysregulated glucose and lipid metabolism in metabolic syndrome adversely affects GBM treatment response.