Annona muricata, also known as graviola, soursop and guanabana, has been widely utilised for the treatment of a range of cancers. The mechanism of action and the efficacy of A. muricata and its constituents in the treatment of cancer have been comprehensively reviewed. The aim of this systematic review was to summarise the available literature that reports on factors related to the safety and tolerability of A. muricata leaf extract and its acetogenins. In-vitro, preclinical animal studies and human studies of any design written in any language were included. Studies that evaluated A. muricata leaf extract and its constituents were searched through the databases Pubmed, Medline and Embase from inception to April 2019. The elaborated item 4 of Consolidated Standards of Reporting Trials statement and Animals in Research: Reporting In vivo Experiments guidelines were used to evaluate the quality of the studies. The results suggest that A. muricata and its constituents have hepatoprotective, neurotoxic, antinociceptive, anti-ulcerative and chemopreventive effects. The dose and duration used in animal studies demonstrating toxicity may not directly translate into the effects in humans. Studies included in this review were judged to be of medium to high quality. The overall outcome of the current review suggests that A. muricata has a favourable safety and tolerability profile. Future studies investigating its use in people diagnosed with a range of cancers are warranted. © 2019 Royal Pharmaceutical Society.