The intranasal administration of nanostructured lipid carriers (NLC) has been suggested as a promising strategy to improve the fast treatment of epilepsy. This route allows drug passage directly from the nose to the brain, avoiding the need of bypassing the blood brain barrier. In addition, the quality-by-design (QbD) approach is a useful tool for the optimization of manufacturing variables, resulting in effective and safe pharmaceutical formulations. Herein, the quality target profile product (QTPP) and critical quality attributes (CQAs) are identified and a risk assessment analysis is conducted to qualitatively detect the most critical material attributes (CMAs) and critical process parameters (CPPs). The aim of this work was to use the QbD approach to optimize a NLC formulation for the nose-to-brain delivery of diazepam, improving the emergency therapy of epilepsy. The studies began with the screening of excipients and the assessment of lipid-drug compatibility. The central composite design was used to evaluate the effects of CMAs (ratio of solid and liquid lipids and amount of emulsifiers) on the CQAs of the NLC formulation (particle size, polydispersity index (PDI), zeta potential (ZP) and encapsulation efficiency (EE)). The results showed that the most adequate ratios of lipids and emulsifiers were 6.65:2.85 and 4.2:0.3 (%, w/w), with values of 84.92 nm, 0.18, -18.20 mV and 95.48% for particle size, PDI, ZP and EE, respectively. This formulation was selected for further studies related to the optimization of CPPs.