Schizophrenic patients often face challenges with adherence to oral regimens. The study aimed to highlight the potentiality of intranasal ethanol/glycerin-containing lipid-nanovesicles (glycethosomes) incorporated into in situ gels for sustaining anti-psychotic risperidone (RS) release. The Box–Behnken Design (BBD) was followed for in vitro characterization. Glycethosomal-based in situ gels were examined by physical, ex vivo, and in vivo investigations. The ethanol impact on minimizing the vesicle size (VS) and enhancing the zeta potential (ZP) and entrapment efficiency (EE%) of nanovesicles was observed. Glycerin displayed positive action on increasing VS and ZP of nanovesicles, but reduced their EE%. After incorporation into various mucoadhesive agent-enriched poloxamer 407 (P407) in situ gels, the optimized gel containing 20% P407 and 1% hydroxypropyl methyl cellulose-K4M (HPMC-K4M) at a 4:1 gel/glycethosomes ratio showed low viscosity and high spreadability with acceptable pH, gel strength, and mucoadhesive strength ranges. The ethanol/glycerin mixture demonstrated a desirable ex vivo skin permeability of RS through the nasal mucosa. By pharmacokinetic analysis, the optimized gel showed eight-fold and three-fold greater increases in RS bioavailability than the control gel and marketed tablet, respectively. Following biochemical assessments of schizophrenia-induced rats, the optimized gel boosted the neuroprotective, anti-oxidant, and anti-inflammatory action of RS in comparison to other tested preparations. Collectively, the intranasal RS-loaded glycethosomal gel offered a potential substitute to oral therapy for schizophrenic patients.