Ayahuasca is a psychedelic plant brew that has been used in Central and South America for centuries. Recently, there has been an increase in "drug tourism" to places where ayahuasca is legally available as well as increased scientific interest in its potential mental and physical health benefits. Despite a growing body of research over the last decade, no studies to date have systematically synthesized the long-term health effects of ayahuasca. Thus, we conducted a systematic review of prospective ayahuasca studies that reported long-term health outcomes. A total of 18 studies were included in the review, with the majority including unselected volunteers attending ayahuasca retreat centers as participants. Across studies, long-term changes were noted in wellbeing/quality of life, depression and other psychiatric symptoms, substance misuse, cognitive flexibility, personality, and prosocial behavior. Although mental health improvements were noted at the population level, studies also reported subsets of participants with persisting psychiatric complications linked to their ayahuasca use. No prospective studies in our search looked at physical health conditions specifically, although one study found a decrease in physical pain symptoms and another lasting neurometabolic changes in the posterior cingulate cortex (PCC). Many of the studies were limited by small sample sizes, unstandardized dosages, no control groups, and nonrandomized study designs that limit interpretability of ayahuasca's potential therapeutic efficacy. Although preliminary research on the health effects of ayahuasca has been promising, future research addressing these limitations is needed to refine our understanding.