Laser interstitial thermal therapy (LITT) has emerged as an alternative for treating glioblastoma (GBM) in patients deemed unsuitable for resection due to deep-seated or eloquent location, age, or comorbidities. However, its safety and efficacy in large-volume, deep-seated, newly diagnosed GBM (nGBM) tumors remain insufficiently studied. Therefore, the authors aimed to assess the outcomes of LITT in the treatment of deep-seated, large-volume nGBM. A retrospective analysis of patients with nGBM who underwent LITT between February 2013 and August 2023 was conducted. Patients with deep-seated tumor volume ≥ 10 cm3 treated with LITT were compared to patients with deep-seated tumor volume < 10 cm3. Demographic, perioperative, and follow-up data were collected and compared among both groups. Kaplan-Meier survival analysis and Cox proportional hazards regression were performed to evaluate the impact of various clinical and treatment-related factors on patient survival. A total of 33 patients in the study group (mean ± SD age 65.7 ± 10.2 years, 58% male) with mean tumor volume 36.0 ± 21.6 cm3 were compared to 23 controls (mean age 67.0 ± 12.5 years, 61% male) with mean tumor volume 5.2 ± 2.7 cm3. There were no significant differences in hospital length of stay (p = 0.494), temporary neurological deficits and edema within 30 days (p = 0.705 and p > 0.999, respectively), 30-day readmissions (p = 0.139), < 30-day complications (p = 0.918), complications between 30 days and 3 months (p = 0.903), and new motor and speech deficits within 3 months (p = 0.883 and p > 0.999, respectively) between the study and control groups. Kaplan-Meier analysis did not reveal any statistically significant difference in overall survival (OS) between groups (p = 0.227). Multivariate analysis indicated that tumor volume did not significantly affect the hazard ratio for individuals undergoing LITT (HR 1.16, 95% CI 0.83-3.29, p = 0.150). This pilot study suggests that LITT is safe for treating patients with large-volume, deep-seated nGBM compared to those with small-volume tumor. Although there appears to be improved OS in patients with smaller lesions with greater EOA, significance was not achieved in this cohort.