Psoriasis is an immune-mediated skin condition. There are many therapeutic options for its treatment; however, none of them is completely effective. Tapinarof is a promising new active substance; it was recently approved by the FDA for the treatment of psoriasis. The aim of our study was to prepare topical nanoformulations of the active substance to improve its bioavailability and therapeutic effect. The biocompatibility investigation of the formulations was carried out by MTT assay, and the size distribution of the preparations was investigated by DLS. In parallel, the rheological properties and the texture were examined, and the in vitro release of tapinarof was assessed by the Franz diffusion method. An in vitro wound healing assay was also carried out to study the drug's properties. Our results show that the preparations were safe on HaCaT cells. The particle size of the formulations was proven to be in the nanoscale range. In the in vitro release studies, nanogel II. showed greater release of the active substance. According to the wound healing assay, incorporation of the drug into nanoformulations increases the antiproliferative and antimigration activity of the drug. Overall, nanoformulations of tapinarof were successfully prepared, and our results suggest that they can be a useful addition to the current therapeutic practice of psoriasis.