Nicergoline (NIC) is a semisynthetic ergot alkaloid derivative applied for treatment of dementia and other cerebrovascular disorders. The efficacy of sesame oil to slow and reverse the symptoms of neurodegenerative cognitive disorders has been proven. This work aimed to formulate and optimize sesame oil-based NIC-nanostructured lipid carriers (NIC-NLCs) for intranasal (IN) delivery with expected synergistic and augmented neuroprotective properties. The NIC-NLC were prepared using sesame oil as a liquid lipid. A three-level, three-factor Box-Behnken design was applied to statistically optimize the effect of sesame oil (%) of the total lipid, surfactant concentration, and sonication time on particle size, zeta potential, and entrapment efficacy as responses. Solid-state characterization, release profile, and ex vivo nasal permeation in comparison to NIC solution (NIC-SOL) was studied. In vivo bioavailability from optimized NIC-NLC and NIC-SOL following IN and IV administration was evaluated and compared. The optimized NIC-NLC formula showed an average particle size of 111.18 nm, zeta potential of -15.4 mV, 95.11% entrapment efficacy (%), and 4.6% loading capacity. The NIC-NLC formula showed a biphasic, extended-release profile (72% after 48 h). Permeation of the NIC-NLC formula showed a 2.3 enhancement ratio. Bioavailability studies showed a 1.67 and 4.57 fold increase in plasma and brain following IN administration. The results also indicated efficient direct nose-to-brain targeting properties with the brain-targeting efficiency (BTE%) and direct transport percentage (DTP%) of 187.3% and 56.6%, respectively, after IN administration. Thus, sesame oil-based NIC-NLC can be considered as a promising IN delivery system for direct and efficient brain targeting with improved bioavailability and expected augmented neuroprotective action for the treatment of dementia.