Irbesartan (IRB), a selective AT1 subtype angiotensin II receptor blocker used for management of hypertension, exhibiting low and variable oral bioavailability because of its poor aqueous solubility. Transdermal delivery is increasingly being used to deliver drugs since it avoids the drawbacks associated with oral delivery. The purpose of the current study was to develop a transdermal gel of IRB through encapsulation of the drug into spanlastics vesicles containing penetration enhancers to enhance transdermal permeation and sustain IRB release. By ethanol injection method, ten IRB loaded spanlastics (IRB-SPs) were prepared; Span 60 was used as the main vesicle component and the used edge activator (EA) was Tween 80. The prepared formulations were studied in regards to entrapment efficiency (EE%), particles size (PS), zeta potential (ZP), polydispersity index (PDI), and in vitro release study. The selected formula (SF) which comprised of Span 60 and Tween 80 at weight ratio of 1:1 and Labrafil as a penetration enhancer, exhibited EE% of 90.06 ± 1.44 %, PS of 311.6 ± 2.45 nm, PDI of 0.536 ± 0.044, and the % drug released after 8 h is 58.2 ± 1.87 %. Transmission electron microscopy confirmed the spherical shape of the prepared spanlastics. Differential scanning calorimetry (DSC) confirmed the drug encapsulation within the spanlastics. The SF and pure drug were incorporated into HPMC K4M based hydrogel (2.5 % w/v). Histopathological and ex-vivo skin permeation studies of hydrogel were assessed as well as its in vitro characteristics. Skin permeation was enhanced by 3.5 folds with the SF loaded gel compared to the control gel. The pharmacokinetic study revealed better bioavailability of the SF-gel by 1.72 and 2.53 fold as compared to the oral suspension and the control gel, respectively. Furthermore, the pharmacodynamic assessment was carried out on systolic blood pressure (SBP) of various IRB formulations in dexamethasone induced hypertensive rat; the antihypertensive effect of SF loaded transdermal gel showed significantly (p < 0.001) much greater blood pressure reduction than the market product’s oral suspension. Finally, spanlastics-based gels could be an excellent way to improve IRB transdermal delivery.