The genus Croton (Euphorbiaceae) encompasses numerous species recognized for their diverse medicinal applications, particularly in pain management. This systematic review aims to compile and analyze the scientific evidence on the antinociceptive properties of Croton species. The review protocol was registered in the Open Science Framework (OSF) associated project: osf.io/z4juf. Using the PRISMA methodology, an exhaustive search was conducted in databases such as PubMed, Scopus, and Web of Science to identify relevant studies published to date. The review includes preclinical studies in animal models that investigate the mechanisms of action and efficacy of Croton extracts and isolated compounds in pain inhibition. The results indicate that 28 Croton species exhibit significant antinociceptive effects, attributed to bioactive compounds such as diterpenes, alkaloids, and flavonoids. These compounds interact with multiple biological pathways, including ion channels, such as TRPV1, K/ATP, and ASIC channels, as well as the inhibition of the synthesis of inflammatory mediators, particularly prostaglandins. This review highlights the potential of Croton as a source of novel analgesic agents and emphasizes the necessity for further clinical studies. Additionally, integrating ethnobotanical and pharmacological knowledge is suggested to develop innovative and effective treatments for pain management.