A biocompatible topical thermo-reversible hydrogel containing Pranoprofen (PF)-loaded nanostructured lipid carriers (NLCs) was studied as an innovative strategy for the topical treatment of skin inflammatory diseases. The PF-NLCs-F127 hydrogel was characterized physiochemically and short-time stability tests were carried out over 60 days. In vitro release and ex vivo human skin permeation studies were carried out in Franz diffusion cells. In addition, a cytotoxicity assay was studied using the HaCat cell line and in vivo tolerance study was performed in humans by evaluating the biomechanical properties. The anti-inflammatory effect of the PF-NLCs-F127 was evaluated in adult male Sprague Daw-ley® rats using a model of inflammation induced by the topical application of xylol for 1 h. The developed PF-NLCs-F127 exhibited a heterogeneous structure with spherical PF-NLCs in the hydrogel. Furthermore, a thermo-reversible behaviour was determined with a gelling temperature of 32.5 °C, being close to human cutaneous temperature and thus favouring the retention of PF. Furthermore, in the ex vivo study, the amount of PF retained and detected in human skin was high and no systemic effects were observed. The hydrogel was found to be non-cytotoxic, showing cell viability of around 95%. The PF-NLCs-F127 is shown to be well tolerated and no signs of irritancy or alterations of the skin’s biophysical properties were detected. The topical application of PF-NLCs-F127 hydrogel was shown to be efficient in an inflammatory animal model, preventing the loss of stratum corneum and reducing the presence of leukocyte infiltration. The results from this study confirm that the developed hydrogel is a suitable drug delivery carrier for the transdermal delivery of PF, improving its dermal retention, opening the possibility of using it as a promising candidate and safer alternative to topical treatment for local skin inflammation and indicating that it could be useful in the clinical environment.