A new series of 5-arylhydrazonothiazole derivatives 5a-d has been synthesized, elucidated, and evaluated for their antidermatophytic activity. The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of the newly synthesized products were investigated against 18 dermatophyte fungal isolates related to Epidermophyton floccosum, Microsporum canis, and Trichophyton rubrum. The morphological alterations induced by the synthesized derivatives singly or conjugated with the monoclonal antibody were examined on spores of T. rubrum using a scanning electron microscope. The efficacy of synthesized derivative 5a applied at its respective MFC alone or conjugated with anti-dermatophyte monoclonal antibody 0014 in skin infection treatment of guinea pigs due to inoculation with one of the examined dermatophytes, in comparison with fluconazole as standard reference drug was evaluated. In an in vivo experiment, the efficiency of 5a derivative conjugated with the antibody induced 100% healing after 45 days in the case of T. rubrum and M. canis-infected guinea pigs.