Daily intranasal administration of resveratrol-conjugated gold nanoparticles at 0.1 mg/kg significantly extended survival and improved motor performance in R6/2 transgenic mice, a well-established Huntington's disease model. The treatment reduced striatal atrophy, decreased toxic protein aggregates, and increased neuroglobin levels while activating CREB and BDNF pathways in medium spiny neurons—the primary targets of Huntington's neurodegeneration. This represents a meaningful advance in neuroprotective delivery systems. The intranasal route bypasses blood-brain barrier limitations that have hampered previous resveratrol trials, while gold nanoparticle conjugation likely enhances stability and targeting. The dual mechanism—direct neuroprotection through enhanced cellular resilience pathways and anti-inflammatory effects through microglial modulation—addresses Huntington's core pathology more comprehensively than single-target approaches. However, translation remains challenging given the aggressive nature of the R6/2 model compared to human disease progression. The 0.1 mg/kg dosing and prodromal-stage intervention timing will need careful consideration for human trials, as will long-term nanoparticle safety profiles. This work validates targeted drug delivery as a promising strategy for neurodegenerative diseases where traditional oral bioavailability limits therapeutic potential.