Background <p>Off-label rectal administration of intravenous diazepam is commonly practiced for acute seizure management in children when FDA-approved rectal gels (e.g., Diastat^® AcuDial) are inaccessible—particularly in low-resource settings like Vietnam. However, such injectable formulations often contain excipients not validated for mucosal use, including propylene glycol and sodium benzoate, which may induce hypersensitivity reactions. Reports of anaphylaxis in this context remain exceedingly rare.</p> Case presentation <p>We describe a case of suspected grade III anaphylaxis in a 14-month-old girl with complex febrile seizure who received 2&#xa0;mg rectal diazepam (injectable formulation, Vidipha, Vietnam). Within five minutes of administration, she developed generalized urticaria, apnea, cyanosis, and hypotonia. Emergency treatment included intramuscular epinephrine, corticosteroids, antihistamines, and mechanical ventilation. She made a full recovery. The diazepam preparation used contained approximately 40% propylene glycol and also included sodium benzoate—both of which have been reported as potential triggers of non–IgE-mediated hypersensitivity reactions, particularly when delivered via mucosal routes.</p> Conclusion <p>This case underscores the potential for life-threatening adverse events following off-label rectal use of injectable diazepam. Emergency clinicians should be aware of excipient-related risks and prioritize safer alternatives such as intranasal midazolam. There is an urgent need for regulatory efforts to improve access to mucosal-safe, pediatric-appropriate benzodiazepine preparations in resource-limited healthcare systems.</p>