Background and Objectives: There is confusion as to which component of the Opuntia spp. cacti has demonstrated anti-hyperglycemic effects or anti-diabetic properties. It is important to clarify these health benefits due to the increasing need for prevention and treatment of chronic diseases. The aim of this review is to identify the effects of Opuntia spp. cacti consumption on biomedical measures; glucose and insulin with consideration of its' components; fruit, leaf and combined or unidentified Opuntia spp. products. Materials and Methods: Prior to commencing the searches, this systematic review was registered with PROSPERO (CRD42018108765). Following the PRISMA 2009 guidelines, six electronic databases (Food Science and Technology Abstracts (EBSCO), Medline, Scopus, CINAHL, Web of Science and Cochrane) were searched for articles investigating the effect of Opuntia spp. consumption on glucose and insulin in humans. Results: Initially, 335 articles were sourced and filtered by exclusion criteria (human interventions, control trials and articles published in English) resulting in 20 relevant articles. The included studies were characterized by such plant components as fruit (n = 4), cladode (n = 12), and other Opuntia spp. products (n = 4), further separated by clinical populations ('healthy', hyperlipidemic, hypercholesterolemic, Type 2 Diabetes Mellitus). The findings of this review indicate variations in effects between cacti components and products. Cladode and select Opuntia spp. products predominately demonstrated significant reductions in serum glucose and insulin, indicating potential as a functional food candidate. Prickly Pear fruit was predominately reported to have no significant effects on glucose or insulin. The quality of evidence appeared to vary based on the type of Opuntia spp. product used. Studies that used specifically the fruit or cladode had high risk of bias, whereas studies which used combined Opuntia spp. products had a lower risk of bias. Numerous mechanisms of action were proposed where positive findings were reported, with emphasis on dualistic glucose-dependent and independent actions, however, mechanisms require further elucidation. Conclusion: Currently, there is a lack of evidence to support the recommendation of using Opuntia spp. fruit products as an alternative or complementary therapy in the reduction of risk or management of Type 2 Diabetes Mellitus. The Cladode does however show promise in potential glucose-lowering effects which warrant further investigation.