Benadryl contains one of several antihistamines and is used for the temporary relief of seasonal and perennial allergy symptoms. It will also help with normal symptoms of insect stings even if there is no allergic reaction. Benadryl is available for oral or topical use.

In the United States and Canada, Benadryl products contain the first-generation antihistamine diphenhydramine. Diphenhydramine is used as an allergy treatment in various forms around the world. It is an H₁ receptor antagonist. Antagonism is achieved through blocking the effect of histamine more than blocking its production or release. Diphenhydramine inhibits most responses of smooth muscle to histamine and acts as a vasoconstrictor by inhibiting the vasodilator effects of histamine. The antagonism may also produce anticholinergic effects, antiemetic effects, and significant sedative side-effects.

In the United Kingdom, Benadryl products contain either the second-generation non-sedating antihistamine acrivastine (marketed as Benadryl Allergy Relief, with a suggested efficacy duration of eight hours) or the non-sedating antihistamine cetirizine (marketed as Benadryl One a Day Relief). Cetirizine is indicated for the relief of symptoms associated with allergy and hives. It is an orally active and selective H₁ receptor antagonist.