Human infection with Orf virus is a rare zoonotic disease in clinical practice, mainly caused by human contact with infected sheep or its pollutants. It is commonly seen in shepherds and slaughterhouse workers. The lesion mainly involves the skin. Since it is rare in clinic and difficult to diagnose and treat, it is easy to be misdiagnosed and underdiagnosed. This paper reports a case of human infection with Orf virus, with locally dense skin lesions. The clinical diagnosis and treatment processes of this case are analyzed, and relevant literatures are reviewed retrospectively, so as to improve clinical understanding on this disease.