The blood–brain barrier (BBB) is the major barrier for brain drug delivery and limits the treatment options for central nervous system diseases. To circumvent the BBB, we introduced the focused ultrasound-mediated intranasal brain drug delivery (FUSIN) technique. FUSIN utilizes the nasal route for direct nose-to-brain drug administration, bypassing the BBB and minimizing systemic exposure. It also uses the transcranial application of ultrasound energy focused at a targeted brain region to induce microbubble cavitation, which enhances the transport of intranasally administered agents at the FUS-targeted brain location. FUSIN is unique in that it can achieve noninvasive and localized brain drug delivery with minimized systemic toxicity. The goal of this chapter is to provide a detailed protocol for FUSIN delivery to the mouse brain.