Background: The role of tumor genomics in influencing treatment outcomes remains a critical area of investigation in personalized medicine. This study is the first to evaluate the relationship between tumor mutational burden (TMB) and driver mutations (DM) in pediatric brain tumors, examining their association with treatment modalities and patient outcomes. Methods: We conducted a retrospective study of 160 pediatric patients (78 males, 82 females) with a median age of 9 years (range: 2 months to 26 years) who were diagnosed with primary CNS tumors across four academic institutions between 2008 and 2023. The analysis included TMB (high TMB ≥3 mutations/megabase, low TMB <3), DM, treatment modality, clinical outcomes, and matching status, defined as the alignment of tumor genomic markers with corresponding pharmacologic targets. Results: Low-grade glioma (42.5%) and high-grade glioma (22.5%) were the most common tumors, followed by medulloblastoma (10.6%), ependymoma (5%), ganglioglioma (4.4%), atypical teratoid rhabdoid tumor (2.5%), and other rare tumor types. Among patients receiving targeted or immunotherapy (N=30), most had matched therapy (N=19) and were found to have no significant survival advantage. High TMB tumors had better survival with standard therapy (p=0.026). Targeted and immunotherapy were used as second or later lines of treatment, with a non-significant trend suggesting better survival in recurrent or progressive disease. Conclusions: This study found no statistical significance linking matched therapy with molecular markers to improved overall survival. Most patients received targeted or immunotherapy as second-line or later treatment. High TMB tumors had better outcomes with standard therapy. The increased resistance and aggressiveness of recurrent tumors complicate the ability to evaluate targeted therapies as initial treatment options.