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There has been increasing attention to the possible association between long-term use of certain antihistamines—especially older, first-generation anticholinergic agents like diphenhydramine—with a higher risk of cognitive decline and dementia. This risk appears to be related to cumulative anticholinergic burden over many years, rather than short-term or appropriate use. At the same time, for patients with mast cell activation and severe allergic or inflammatory symptoms, antihistamines can be essential for symptom control and quality of life. The key is thoughtful selection of agents, favoring newer, less anticholinergic medications when possible, using the lowest effective dose, and regularly reassessing the ongoing need, so that potential long-term risks are balanced against very real short-term benefits. This information is for educational purposes only and is not medical advice; patients should always discuss medication decisions with their own healthcare provider.