Background: A number of randomised in vivo trials have to date investigated the health impacts of the genetic variants A1 and A2 of bovine β-casein. The primary difference between these two genetic variants is the mutation leading to an amino acid exchange at a position 67 in the peptide chain. This systematic review evaluated the effects of bovine milk, β-casein and pure β-casomorphin7, in the form of orally administered nutritional ingredients, on possible incidence and risk for chronic digestive discomfort and development of incurable conditions and diseases in human and animal randomised controlled trials. Scope and approach: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, searches were performed for publications across 7 electronic databases (Scopus, Embase, Web of Science, Medline, EBSCO, PubMed, and Cochrane) up to and until July 2020, to identify randomised controlled trials. The subsequent search results were screened for relevance firstly by title, then abstract, and the chosen ones by full text, with additional screening of included articles reference lists. Key findings and conclusions: In total 2006 peer-reviewed journal articles were identified and after applying exclusion criteria, 19 studies were deemed suitable for inclusion. Human-based and animal-based results from the clinical in vivo studies demonstrated that consumption of A2 β-casein milk can lead to improved tolerance of milk via decline in the ubiquity of gut related discomfort. However, the exact mechanism for these effects or specific individuals that may benefit from A2 β-casein milk as opposed to A1 β-casein milk is still poorly understood. Notably, consumption of A2 β-casein milk had very low to completely no effect on the other health statuses investigated, particularly non-communicable diseases, such as cardiovascular diseases, neurological disorders, and diabetes. Based on current data, there is not sufficient evidence to merit public health authority recommendations related to the consumption and health associations of A1 β-casein milk or A2 β-casein milk. Interestingly, regardless of the scientific evidence between A2 β-casein milk and health, this milk continues to gain prominence on the market, thus further functional research is required to understand the mechanisms of action of these identified peptides and gene variants and any implications A1 or A2 β-casein milk may have on human health and techno-functional properties of milks.