Diphenhydramine is an antihistamine mainly used to treat allergies. It can also be used for insomnia, symptoms of the common cold, tremor in parkinsonism, and nausea. It is used by mouth, injection into a vein, injection into a muscle, or applied to the skin. Maximal effect is typically around two hours after a dose, and effects can last for up to seven hours.

Common side effects include sleepiness, poor coordination and an upset stomach. Its use is not recommended in young children or the elderly. There is no clear risk of harm when used during pregnancy; however, use during breastfeeding is not recommended. It is a first generation H1-antihistamine and ethanolamine and works by blocking certain effects of histamine. Diphenhydramine is also an anticholinergic.

Diphenhydramine was first made by George Rieveschl and came into commercial use in 1946. It is available as a generic medication. It is sold under the trade name Benadryl, among others. In 2017, it was the 241st most commonly prescribed medication in the United States, with more than two million prescriptions.