Acute dystonia has notably been a challenge in the emergency unit. Drug-induced dystonia is reported in a limited number of cases in the literature. Rarely, diphenhydramine was found to be the culprit. We report the case of a 25-year-old female patient who developed an acute dystonic reaction following the administration of 25 mg of intravenous diphenhydramine as a treatment for an allergic reaction. The patient was given 5 mg diazepam, admitted for monitoring, and discharged home. Diphenhydramine-induced acute dystonia is a user drug-induced threatening reaction that warrants further investigation on the metabolism of these drugs and the contributing phenotypes to this adverse reaction.