The systemic administration of methotrexate (MTX), a commonly used, antineoplastic drug which is also used in cutaneous disorders, is primarily associated with prolonged retention in the body and consequently with side effects. Innovative drug delivery techniques and alternative administration routes would therefore contribute to its safe and effective use. The general objective of this study is thus the development of MTX-based preparations for the topical treatment of skin disorders. MCM-41-like nanoparticles (MSN), are herein proposed as carriers which can improve the cutaneous absorption and hence the bioavailability and efficacy of MTX. The MTX/MSN complex, prepared via the impregnation procedure, has been physico-chemically characterized, while its cell cultures have had their biocompatibility and bioactivity tested. Furthermore, a series of stable MTX-based dermal formulations has been developed, some containing shea butter, a natural fat. Ex-vivo porcine skin absorption and the transepidermal permeation of MTX have also been monitored in a variety of media using Franz diffusion cells. Interestingly, the epidermal accumulation of the active molecule was increased by its inclusion into MSN, regardless of the surrounding medium. Furthermore, the presence of shea butter enhanced the skin uptake of the drug both in the free and in the loaded form.