Clozapine is commonly used to treat schizophrenia but it is having issues of low oral bioavailability (<27%), degradation in GI environment and high hepatic first-pass metabolism. The present research work aimed to overcome the above issues, by designing tailored clozapine loaded nanostructured lipid carriers (NLCs) and deliver them to the brain via intranasal pathway. The clozapine NLCs were prepared using high-speed homogenization method. The 3² full factorial design was chosen to optimize the size (178 nm) and entrapment efficacy (77.4 %) of NLCs by selecting Precirol ATO 5 = 495 mg (solid lipid), oleic acid = 62 μl (liquid lipid) and Tween 80 = 1.42 % (surfactant). The release of clozapine from NLCs was sustained up to 48 h (77.18 %). In contrast to orally administered clozapine tablet (Cmax = 6.26 2.5 g/gm, tmax = 3 h), intranasal administration of NLCs resulted in substantial therapeutic clozapine concentration in brain tissue (Cmax = 73.8 2.5 g/gm, tmax = 2 h). The 6.15-fold increase in relative bioavailability suggests that NLCs bypassed hepatic first-pass metabolism and overcome the blood-brain barrier (olfactory and trigeminal nerve transport). Based on our findings, we conclude that the engineered clozapine-loaded NLCs, along with the noninvasive nose-to-brain delivery approach, may help with clozapine brain targeting for schizophrenia treatment.