Sesquiterpernes are natural compounds widely distributed in plants rich in essential oils; among these compounds, alpha-humulene and its isomers stand out for their multiple pharmacological properties and for their uses in the cosmetics, perfumery and food industries. The present study aimed to conduct a systematic review (SR) in order to identify the pharmacological and toxicological activities of alpha-humulene and its isomers. This SR was carried out in accordance with the PRISMA guidelines. The bibliographic search was performed using PubMed, Scopus and Web of Science databases. The inclusion criteria used were: original articles from preclinical and clinical studies that investigated the pharmacological activities and toxicological effects of alpha-humulene and its isomers, which were written in English, Portuguese and Spanish. The initial search resulted in 5165 articles, of which 46 were selected for final analysis. After grouping into categories by activity presented, 41% of the investigated articles reported that alpha-humulene and its isomers had antitumor activity, followed by antiinflammatory and antimicrobial activities (20% for both), other pharmacological activities (15%) and potential toxic (2%). This SR is the first developed grouping studies on the pharmacological and toxicological activities of this group of compounds. In this perspective, it is concluded that alpha-humulene, as well as its isomers, have different pharmacological activities, listing them as an important precursor for new therapies. However, there is still a need for further toxicological investigation on these compounds, in order to ensure safety for their use.