The global rising incidence of skin mycosis especially dermatophytes currently affects more than 20–25% of the world population. It is believed that nanotechnology can aid in the efficient treatment of this skin disease. The present study, therefore, aimed to employ nanostructured lipid carriers (NLCs) in a gel formulation for a more effective delivery of Zataria multiflora (ZM) essential oils through the skin to manage mild to moderate cutaneous dermatophytosis. Zataria multiflora-loaded nanostructure lipid carriers (ZM-NLCs) were prepared and optimized by utilizing an ultrasonic probe approach and formulated the ZM-NLCs as a 1% w/w carbopol gel after confirming the NLCs-related characteristics. In vitro antifungal susceptibility testing was performed on 20 common dermatophyte species based on the CLSI M38-A3 guidelines. A total of 80 volunteers (40 volunteers from each gender, equally divided into two groups: ZM-NLCs gel and placebo receivers) participated in this clinical randomized, double-blind placebo-controlled study. Clinical manifestations (itching, scaling, size of lesion and inflammation), as well as mycological findings such as KOH-direct examination test and culture, were evaluated after 2 and 4 weeks of topical application. Molecular identification of the strains isolated from the patient's lesions was also performed to the species level using a PCR-RFLP method. A mono-dispersed suspension of spherical nanoparticles with zeta potential, Z-average and PDI index of −26.6 ± 7.7 mV, 273.5 ± 4 nm and 0.33 ± 0.03, respectively was achieved with no cytotoxicity. Apart from the significant inhibitory effect of ZM-NLCs on fungal growth, the application of the ZM-NLCs gel resulted in an effective diminution in inflammation (87.5%), itching (90%) and scaling (95%) among the volunteers after 4 weeks. The aforementioned signs/symptoms were significant when compared to the patients receiving a placebo (p < 0.005). A reduction/disappearance of the lesion was also significantly reported in the ZM-NLCs gel receivers. Compared with placebo receivers, meaningful negative results for both direct examination and culture were observed (17.5% vs 70% for KOH-direct examination and 12.5% vs 57.5% for culture) for patients who received ZM-NLCs gel after 2 weeks of prescription. PCR-RFLP outputs revealed T. mentagrophytes/interdigitale complex as the predominant isolated species from cutaneous lesions. In conclusion, Zataria multiflora-NLCs gel application displayed a more rapid cure time with no adverse side effects compared to placebo demonstrating the efficacious nature of NLCs.