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Poor solubility and appreciable first-pass metabolism have limited the oral bioavailability of nebivolol. The objective of the current investigation was to design, formulate, and optimize a hydrogel-based transdermal system for nebivolol using factorial design and compare its pharmacokinetics with oral suspension. Hydrogel formulations (F1&#8722;F8) were prepared by varying the amounts of gellan gum, carbopol, and polyethylene glycol. A 2³ full factorial design was used to assess the effect of independent variables such as gellan gum, carbopol, and polyethylene glycol 400 on dependent variables like viscosity, <i>in vitro</i> release, and <i>ex vivo</i> permeation after 2 h at two levels. Optimized gel (F7), containing nebivolol hydrochloride (75 mg), gellan gum (300 mg), carbopol (150 mg), polyethylene glycol 400 (20 &#181;L), tween 80 (1 mL), ethanol (10 mL), and water (up to 30 mL) was selected and evaluated in albino rats. The physicochemical properties of F7 (pH: 7.1 &#177; 0.15, viscosity: 8943 &#177; 116 centipoise, drug content: 98.81% &#177; 2.16%) seem ideal for transdermal application. It was noticed that the concentration of carbopol has a more significant role than gellan gum in gel viscosity. A biphasic release pattern was exhibited by gels, and the release rate was mainly influenced by the concentration of gellan gum. Greater transdermal flux (30.86 &#177; 4.08 &#181;g/cm²/h) was observed in F7 as compared with other prepared gels. Noticeable enhancement in <i>AUC</i>_0-&#945; value (986.52 &#177; 382.63 ng.h/mL; <i>p</i> &lt; 0.01) of transdermal therapy (~2-fold higher compared with oral administration) established the potential of F7 to improve the rate and extent of nebivolol delivery. The overall results demonstrated here signify that F7 could be a feasible alternative to oral therapy of nebivolol.