Certain challenges like the presence of highly complex structure (blood-brain barrier (BBB)), P-glycoprotein efflux, and the particular enzymatic activity stand in the way of the successful delivery of the drug moieties to the brain and make them fruitless. Many efforts have been conducted to overcome the previous. Direct delivery of drugs to the brain after the intranasal application is one of those strategies since it holds a great hope to raise the chances of drug moieties to the brain. Nanoparticles could be the potential to improve nose-to-brain drug delivery since they are able to protect the encapsulated drugs from biological and/or chemical degradation and increase their penetration across biological barriers. Based on the fact that neuroinflammation is associated with neuron death and neurodegenerative diseases like Alzheimer’s, nonsteroidal anti-inflammatory drugs (NSAIDs) might play a positive role in the disease. The present study aimed to employ the QbD approach for the first time in optimizing polymeric and lipid-based nanoparticles for the nose-to-brain delivery of Meloxicam (MEL), and to perform a comparison between the pure drug and the formulated nanosystems regarding dissolution profiles, permeability, and mucoadhesiveness.