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/cm2) and drug flux (39.38 μg/cm2.h−1) through fresh sheep nasal mucosa in comparison to control gel (150.76 μg/cm2 and 14.44 μg/cm2.h−1, 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.