Introduction: More emphasize was given in the present work is application of QbD tools and DoE approach. The existing study was aimed towards development and characterization of Midazolam (MZM) loaded microemulsion (ME) for brain delivery through nasal route.Methods: Different QTPP and CQAs were identified initially and REM was prepared. Further D optimal design was employed with concentration of Oil (X1), concentration of Smix (X2) and concentration of water (X3) as significant independent variables (IVs). Globule size (Y1), %Transmittance (Y2) and Viscosity (Y3) were kept as important CQAs.Results: MLR models revealed that selected IVs have great impact on Y1 and Y3, especially main and interactive effect. The results were supported by contour plots (2D and3D) and predicated Vs actual plot. % PE values for check point batches were found less than 5% indicating accuracy of evolved MLR models. Further, control space was mapped from design space of overlay plot and out of control space, one batch was optimized and revised REM was prepared. Revised REM showed low risk potential of various IVs on selected CQAs. Optimized batch was tested for zeta potential, conductivity, Polydispersity index, viscosity, refractive index, isotropic number. Moreover, ex vivo permeation using sheep nasal mucosa in simulated nasal fluid (SNF). The study revealed that superior permeation than Midazolam suspension which is attributed to the incorporation of MZM into ME carrier.Conclusion: So, in a nutshell, it can be concluded that application of QbD approach and DoE concepts in MZM loaded ME yielded design space which will be useful for error free scale up plan implementation.