Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and impaired daily functioning, primarily associated with β-amyloid aggregation, tau hyperphosphorylation, oxidative stress, and neuroinflammation. Current therapies provide only symptomatic relief and fail to modify disease progression, highlighting the urgent need for novel therapeutic approaches. Baicalein, a natural flavonoid derived from Scutellaria baicalensis, exhibits potent antioxidant, anti-inflammatory, and anti-amyloid properties, making it a promising neuroprotective candidate. However, its clinical application is limited by poor aqueous solubility, rapid metabolism, and restricted penetration across the blood–brain barrier (BBB). To overcome these challenges, the present study focused on the development of a Baicalein-loaded in-situ nasal gel for nose-to-brain delivery. The in-situ gel system, composed of Poloxamer 407 and Carbopol 934, was designed to undergo sol-to-gel transition at physiological nasal temperature and pH, thereby enhancing mucosal retention and sustained drug release. Formulations were optimized based on clarity, gelling capacity, viscosity, drug content, and mucoadhesion. In vitro release and ex vivo permeation studies confirmed controlled release and improved nasal absorption. Histopathological evaluation demonstrated safety and non-irritant nature of the gel on nasal mucosa. In vivo pharmacokinetic studies in rats revealed significantly higher brain bioavailability of Baicalein from the nasal gel compared to oral administration. Behavioral assessments, including Morris water maze and Y-maze tests, indicated enhanced memory performance in AD-induced rats treated with the formulation. Biochemical assays further confirmed reduced acetylcholinesterase activity and improved antioxidant defense in brain tissues. Overall, the developed Baicalein-loaded in-situ nasal gel showed promising neuroprotective effects and offers a novel, non-invasive, and patient-friendly approach for managing Alzheimer’s disease. Future studies are warranted to evaluate long-term efficacy and clinical translation potential.