Cardio-metabolic diseases (CMD) are a spectrum of diseases (e.g., type 2 diabetes, atherosclerosis, non-alcohol fatty liver disease (NAFLD), and metabolic syndrome) that are among the leading causes of morbidity and mortality worldwide. It has long been known that bile acids (BA), which are endogenously produced signalling molecules from cholesterol, can affect CMD risk and progression and directly affect the gut microbiome (GM). Moreover, studies focusing on the GM and CMD risk have dramatically increased in the past decade. It has also become clear that the GM can function as a “new” endocrine organ. BA and GM have a complex and interdependent relationship with several CMD pathways. This review aims to provide a comprehensive overview of the interplay between BA metabolism, the GM, and CMD risk and progression.