The delivery of ibuprofen into and through the skin from novel formulations containing TEMPO-oxidized cellulose nanofibril-based (TOCN) gels was compared to that from two conventional and commercially available products. The gels were evaluated in-vitro (using both silicone membranes, and pig skin) and in-vivo in human volunteers. All gels showed consistent behaviour in a standard in vitro release test. The stratum corneum (SC) uptake and skin penetration of ibuprofen in vitro from the novel gels and the marketed formulations were generally comparable even though the drug loading in the TOCN-based vehicles was only 20% of that in the ‘reference’ products. In vivo, the new gels appeared to enhance drug uptake into the SC following a relatively short application time, again matching the performance of the commercial formulations. Taken together, the results of this research provide proof-of-concept for the idea that the sustainable, oxidised cellulose gels may provide more efficient drug delivery into and through the skin, thereby improving drug utilisation and reducing potential adverse effects when such formulations are applied chronically over large skin areas.