Ayahuasca is a pan-Amazonian botanical hallucinogenic decoction made from a mixture of the bark of the Banisteriopsis caapi plant, containing a monoamine oxidase inhibitor, and Psychotria viridis (Rubiaceae) or Diplopterys cabrerana shrubs containing a serotonergic 2A receptor agonist, N,N-dimethyltryptamine, a powerful psychoactive substance. Ayahuasca is a traditional psychoactive sacrament that has been used for shamanic ceremonies for centuries. Ayahuasca is acclaimed for spiritual and psychotherapeutic benefits and is gaining popularity in the United States. Potential risks involved with usage of this hallucinogenic drug include psychotic episodes related to N,N-dimethyltryptamine and serotonin syndrome, which can be potentially life threatening. The consequences of ayahuasca use remain uncertain because of poor quality control, unpredictability, and polydrug interactions. Nurses, advanced practice nurses, and other healthcare providers working in outpatient settings, hospitals, and treatment centers need to be familiar with the pharmacology, possible drug interactions, and management for ayahuasca ingestion for optimal decision making. Nurses are well positioned to facilitate understanding and to advise and educate the public about the potential risks associated with ayahuasca ingestion.