Atopic dermatitis (AD) is a systemic multifactorial genetically determined inflammatory skin condition characterized by an impairment of the epidermal barrier and Type 2 inflammation. AD is highly prevalent, especially among children. Many authors consider AD as the initial stage of the atopic march, which typically manifests in the first year of life. Topical agents such as topical glucocorticosteroids (TCS) and topical calcineurin inhibitors (TCIs) are the first-line treatments for AD. In recent years, there has been an increasing use of modern systemic anti-inflammatory agents, such as monoclonal antibodies and Janus kinase inhibitors. Modern TCS and their combinations, have a proven high safety profile. However, available data on adverse events associated with their use often lead patients and their parents to develop a negative, phobic attitude towards treatment with these drugs. Zinc pyrithione, an activated form of zinc, is a safe and highly effective medication with anti-inflammatory, antifungal, and antibacterial properties. This article presents two clinical cases of moderate to severe ad in children, demonstrating the effectiveness of using activated zinc pyrithione in comprehensive therapy for this condition.