Owing to its poor solubility and oral bioavailability, etodolac (ETD), a selective COX-2 inhibitor, was formulated in high-dose oral tablets, which affect the gastrointestinal tract and cause a peptic ulcer and bleeding. Therefore, the topical administration of such a drug is an alternative route of administration. In the present work, we aimed to increase the solubility and enhance the dissolution rate of ETD through its adsorption on the surface of an inert adsorbent carrier, Flourite R (FR). Three ratios of ETD:FR were 1:1, 5:1, and 10:1, w/w. The ETD-FR adsorbates were characterized and evaluated, using different techniques such as X-ray and DSC. Three different gelling bases were used to construct the different hydrogel systems loaded with the medicated adsorbates. The hydrogel systems were subjected to different physicochemical characterizations, such as visual inspection, pH determination, and the studies of viscosity, spreadability, and extrudability. Moreover, the in vitro release and in vivo anti-inflammatory effects on rats were studied and correlated. The results revealed that the solubility of ETD adsorbates was significantly improved, with an excellent dissolution rate of 100% was achieved within 5 minutes compared to its original dissolution profile of 50% after 3 h. The data output of the DSC and X-ray indicated the conversion of ETD from the crystalline form into an amorphous one via the adsorption process had a major role in ETD improvement solubility. The hydrogels’ bases-incorporated ETD-adsorbates were significantly providing a remarkable improvement of its in vitro release rates compared to the plain ETD. The in vivo anti-inflammatory activities of constructed hydrogel systems were recorded at higher values compared with indomethacin capsules, with an extended duration of action (8 h). In conclusion, the obtained data confirmed that the modified hydrogel systems are promising vehicles for topical application of ETD in an effective and safe manner.