The purpose of study was to exploit distinctive features of nasal administration route to boost agomelatine permeation and upgrade its anti-depressant action after being embedded in Brij-enriched novasomes (NVs) as non-phospholipid vesicular systems. Different amounts and types of excipients were used to evaluate NVs using definitive screening design (DSD). Optimal NV was incorporated in thermosensitive in-situ gels containing poloxamer 407 (P-407) and hydroxypropyl methyl cellulose (HPMC). After evaluation of novasomal in-situ gels (NVGs), optimal NVG was subjected to ex-vivo, in-vivo, and biochemical investigations. Results showed significant increase in entrapment capability (EC%), particle size (P.S), and zeta potential (Z.P) of NVs after increasing free fatty acid, surfactant, and cholesterol amounts. The capability of Brij to improve fluidization of lipid bilayers, decrease P.S, and increase Z.P was observed. Lipohilicity, EC%, and Z.P of Brij 56-enriched NVs were higher than those containing Brij 35. Gradual increase in HPMC concentration and gel/NV ratio led to marked decrease in gelation time and spreadability and increase in gel strength and viscosity values of NVGs. Optimal NVG9 displayed higher permeation profile (538.34 μg/cm) and drug flux (39.38 μg/cm.h) through fresh sheep nasal mucosa in comparison to control gel (150.76 μg/cm and 14.44 μg/cm.h, respectively). Rats treated with nasal optimal NVG9 manifested increased sucrose preference (SP) percent (80.73%) and levels of dopamine (50.42 ng/g) and serotonin (44.92 ng/g) with decreased low latency time values (5.86 min). This study confirmed the in-vivo safety and amplification of precognitive and anti-depressant action of agomelatine after intranasal administration.