Schizophrenia, a complex neuropsychiatric disorder originating in the central nervous system, poses significant therapeutic challenges primarily due to the restrictive nature of the blood-brain barrier (BBB). In this study, a fisetin-loaded mucoadhesive microemulsion (fisetin-MME) was successfully developed and optimized via Box-Behnken Design (BBD) to enhance the solubility and brain-targeting potential of fisetin following intranasal administration. The optimized formulation exhibited a mean droplet size of 64.0 nm ± 0.05, a polydispersity index (PDI) of <0.5, and high entrapment efficiency (94.9%), alongside favorable thermodynamic stability, rheological characteristics, and mucoadhesive strength (3.24 ± 0.95 g). Physicochemical characterization by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FT-IR), and transmission electron microscopy (TEM) confirmed the structural integrity and compatibility of the formulation. A validated reverse-phase high-performance liquid chromatography (RP-HPLC) method consistently quantified fisetin with a retention time of 6.01 ± 0.23 min. The fisetin-MME demonstrated enhanced release (85.2 ± 2.345%) and nasal mucosal permeation (87.6 ± 0.25%), with significantly improved flux (40.23 ± 0.06 μg/cm/h) and permeability coefficient (81.23 × 10 cm/s), indicating efficient transmucosal transport. Pharmacokinetic evaluation revealed a marked improvement in both systemic and brain bioavailability following intranasal administration, with a brain C_max of 261.53 ± 0.14 ng/g and AUC-t of 2564.0 ± 232.0 h·ng/g, surpassing the reference standard (C_max of 228.50 ± 0.36 ng/g; AUC-t of 2257.6 ± 245.9 h·ng/g). Behavioral assessments, including the Forced Swim Test and Balance Beam Test, demonstrated significant amelioration of schizophrenia-like symptoms, including hyperlocomotion, catalepsy, and impaired motor coordination, with fisetin-MME showing superior neuroprotective and antidepressant effects compared to the standard drug by Day 14 ( < 0.001). Histopathological analysis further supported these findings, demonstrating marked neuroprotective effects in the cortical and hippocampal regions, as evidenced by reduced neuronal degeneration and attenuation of neuroinflammatory markers. These results highlight the potential of intranasally delivered fisetin-MME as a promising nanotherapeutic strategy for the management of schizophrenia.