The study investigated usage of hydrogel of an anionic polymer xanthan gum for design of ibuprofen-loaded hydrogel-thickened microemulsions (HTMs) from the nonionic oil-in-water microemulsion (M). Xanthan gum demonstrated the performances of a thickening agent in physically stable HTMs at 5 ± 3 °C, 20 ± 3 °C, and 40 ± 1 °C during 6 months. The results of physicochemical characterization (pH, conductivity, rheological behaviour, spreadability) indicated that HTMs containing 0.25–1.00% of the polymer had colloidal structure with oil nanodroplets of 14.34 ± 0.98 nm (PdI 0.220 ± 0.075) dispersed in aqueous phase thickened with the polymer gel network which strength depended on the polymer concentration. HTMs with ibuprofen (5%) were evaluated as percutaneous drug delivery carriers. In vitro ibuprofen release from HTMs followed zero order kinetic (r > 0.995) for 12 h, while the referent hydrogel was described by Higuchi model. The HTM with optimized drug release rate and spreadability (HTM1) and the polymer-free microemulsion (M) were assessed and compared with the referent hydrogel in in vivo studies in rats. HTM1 and M were significantly more efficacious than reference hydrogel in producing antihyperalgesic and at lower extent antiedematous activity in prophylactic topical treatment protocol, whilst they were comparable in producing antihyperalgesic/antiedematous effects in therapeutic protocol. Topical treatments produced no obvious skin irritation.