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Glioblastoma multiforme remains one of the most aggressive and lethal central nervous system malignancies, primarily due to the restrictive nature of the blood-brain barrier which severely limits the efficacy of systemically administered chemotherapeutics. To address this critical challenge, this study aims to overcome the limitations of conventional glioblastoma treatment by developing solid lipid nanoparticles (SLNs) co-loaded with temozolomide and carmustine for targeted intranasal administration. The developed SLNs were synthesized and comprehensively evaluated for biodistribution and pharmacokinetics in mice following nose-to-brain delivery. Drug concentrations in the brain and peripheral tissues were quantified using a robust and validated HPLC method. Therapeutic efficacy was further investigated in an in vivo glioblastoma model established by intracerebral U87MG cell implantation. Tumor progression was monitored via precise volume measurements and survival analysis, while the safety profile was assessed through comprehensive acute and subacute toxicity studies. Pharmacokinetic analysis confirmed effective brain tissue distribution and sustained drug levels. Furthermore, the dual-loaded SLN treatment demonstrated a significant reduction in tumor volume and remarkably extended survival rates compared to the control and conventional treatment groups. Ex vivo pathological evaluations and systemic toxicity studies indicated no mortality or gross organic damage at the tested doses, suggesting an acceptable systemic safety profile under the evaluated conditions. However, further rigorous evaluations regarding local nasal mucosal toxicity and long-term renal accumulation are required to fully establish the safety limits of this carrier system. Overall, intranasally administered SLNs provide a promising nanoparticle-based strategy that offers a viable, low-toxicity alternative to improve clinical outcomes in aggressive brain tumors.