A PEGylated Tween 80–functionalized chitosan–lipidic (PEG-T-Chito-Lip) nano-vesicular hybrid was developed for intranasal administration as an alternative delivery route to help improve the poor oral bioavailability of BCS class-III model/antiemetic (metoclopramide hydrochloride; MTC). The influence of varying levels of chitosan, cholesterol, PEG 600, and Tween 80 on the stability/release parameters of the formulated nanovesicles was optimized using Draper-Lin Design. Two optimized formulations (Opti-Max and Opti-Min) with both maximized and minimized MTC-release goals, were predicted, characterized, and proved their vesicular outline
via
light/electron microscopy, along with the mutual prompt/extended
in-vitro
release patterns. The dual-optimized MTC–loaded PEG-T-Chito-Lip nanovesicles were loaded in intranasal
in-situ
gel (ISG) and further underwent
in-vivo
pharmacokinetics/nose-to-brain delivery valuation on Sprague-Dawley rats. The absorption profiles in plasma (plasma-AUC
0-∞
) of the intranasal dual-optimized MTC–loaded nano-vesicular ISG formulation in pretreated rats were 2.95-fold and 1.64-fold more than rats pretreated with orally administered MTC and intranasally administered raw MTC-loaded ISG formulation, respectively. Interestingly, the brain-AUC
0-∞
of the intranasal dual-optimized MTC–loaded ISG was 10 and 3 times more than brain-AUC
0-∞
of the MTC-oral tablet and the intranasal raw MTC-loaded ISG, respectively. It was also revealed that the intranasal dual-optimized ISG significantly had the lowest liver-AUC
0-∞
(862.19 ng.g
−1
.h
−1
) versus the MTC-oral tablet (5732.17 ng.g
−1
.h
−1
) and the intranasal raw MTC-loaded ISG (1799.69 ng.g
−1
.h
−1
). The brain/blood ratio profile for the intranasal dual-optimized ISG was significantly enhanced over all other MTC formulations (P < 0.05). Moreover, the 198.55% drug targeting efficiency, 75.26% nose-to-brain direct transport percentage, and 4.06 drug targeting index of the dual-optimized formulation were significantly higher than those of the raw MTC-loaded ISG formulation. The performance of the dual-optimized PEG-T-Chito-Lip nano-vesicular hybrids for intranasal administration evidenced MTC-improved bioavailability, circumvented hepatic metabolism, and enhanced brain targetability, with increased potentiality in heightening the convenience and compliance for patients.