Psoriasis is a chronic inflammatory disease that is becoming widespread and is associated with many kinds of additional severe diseases. The present study aimed to develop a methotrexate-loaded almond oil-based nanoemulsion formulation (MTX NE) for topical administration. The drug-loaded nanoemulsion formulation was prepared by high shear homogenization technique. The formulation's stability, as well as other physical and chemical characteristics, including entrapment effectiveness, drug release kinetics, skin permeability, skin irritation, and in vivo evaluation of the optimized formulation, was assessed. Additionally, imiquimod-induced psoriasis in rats was employed to investigate the efficacy of MTX NE against skin disorders. The MTX NE formulation was developed with a particle size of 18.74 ± 9.748 nm, a polydispersity index (PDI) of 0.198 ± 0.01, and an average entrapment efficiency of 79.65 ± 3.84%. The release kinetics model estimates 81.08% drug release at pH 5.5 after 24 h. The major layers of the skin, the epidermis, and dermis were successfully fluidized by the optimized MTX NE formulation, as shown by FTIR results, most likely enhancing drug retention and permeability. However, since Tween 80 and PEG 400 are well-known penetration enhancers, their application greatly accelerates these effects. Permeation data indicate that after 24 h, methotrexate was released from the nano-emulsion at 76.83 ± 4.98 g/cm