Netherton syndrome (NS) is a rare autosomal recessive genodermatosis caused by pathogenic mutations in the serine protease inhibitor Kazal-type 5 () gene, leading to impaired skin barrier function and immune dysregulation. It is characterized by congenital ichthyosis, trichorrhexis invaginata, and severe atopy. Herein, we present the case of a young boy with NS, confirmed by genetic analysis revealing a homozygous splice site mutation in (c.1302+5G>C). The patient was treated with intravenous immunoglobulin due to frequent infections that required multiple hospital admissions. When he was 6 years old, dupilumab was added to reduce skin inflammation and improve skin barrier function before food reintroduction. He demonstrated substantial clinical benefits, with marked relief from pruritus resulting in better quality of life. Additionally, he exhibited notable hair growth. Serologically, total his serum IgE levels decreased from 1078 IU/mL to 55.8 IU/mL following dupilumab therapy. This case highlights the potential benefits of an integrated therapeutic approach in management of this challenging condition.