Nanogels combine the properties of hydrogels and nanocarrier systems, resulting in very effective drug delivery systems, including for cutaneous applications. Cyclodextrins (CDs) have been utilised to enhance the nanogels’ loading ability towards poorly soluble drugs and promote/sustain drug release. However, formation of CD-based nanogels requires the use of specially modified CDs, or of crosslinking agents. The aim of this work was to develop a CD-based nanogel to improve the cutaneous delivery of ibuprofen by using the soluble β-cyclodextrin/epichlorohydrin polymer (EPIβCD) without adding any potentially toxic crosslinker. The use of EPIβCD enabled increasing ibuprofen loading due to its complexing/solubilizing power towards the poorly soluble drug and prolonging drug release over time due to the nanogel formation. DLS analysis proved that EPIβCD allowed the formation of nanostructures ranging from 60 up to 400 nm, depending on the gelling agent type and the gel preparation method. EPIβCD replacement with monomeric HPβCD did not lead in any case to nanogel formation. Permeation experiments using skin-simulating artificial membranes proved that the EPIβCD-based nanogel enhanced ibuprofen solubility and release, increasing its permeation rate up to 3.5 times, compared to a reference formulation without CD and to some commercial gel formulations, and also assured a sustained release. Moreover, EPIβCD replacement with HPβCD led to a marked increase in drug solubility and initial release rate, but did not provide a prolonged release due to the lack of a nano-matrix structure controlling drug diffusion.