Present investigation explores the potential of nanostructured lipid carriers (NLCs) for nose to brain delivery of rivastigmine (RV), which is further enhanced by incorporating into an in situ gelling system, increasing retention in nasal cavity. NLCs having particle size of 123.2 ± 2.3 nm, entrapment efficiency of 68.3 ± 3.4%, and zeta potential of 32 ± 1.2 mV was fabricated by a scalable method. Pharmacokinetics showed sustained release of intranasal (IN) and intravenous (IV) NLCs compared with RV solution by same route, with significantly higher AUC and Thalf. Biodistribution indicated blood brain barrier penetrating potential of IV NLCs (457.24 ± 38.41.12 ng/mL) and IN NLCs (736.42 ± 34.54 ng/mL) with 4.6 and 5.3-fold enhancement in brain concentrations compared with IV and IN solution of RV. Similar results reflected in pharmacodynamics, indicating faster regain of memory loss in amnesic mice with 5-fold decrease in escape latency with NLCs compared with plain RV solution by IV and IN routes respectively. Sub-acute toxicity studies demonstrated safety of developed formulations to vital organs without any hematological and biochemical changes compared with control group. Moreover, nasal toxicity studies of NLCs showed no signs of inflammation, maintaining the integrity of ciliary epithelial cells, thus confirming safety of the formulation for its intended nasal application.