Obesity is a systemic disease and represents one of the leading causes of death worldwide by constitutingthe main risk factor for a series of non-communicable diseases such as type 2 diabetes mellitus (T2DM),cardiovascular diseases and dyslipidemia. Lifestyle interventions have been attempting to prevent T2DM andobesity but are difficult to maintain by most patients. However, the recent focus on the intestinal microbiotaand its important role in the host’s metabolism provides a new key for improving metabolic health. Modulatingthe composition of the gut microbiota was proposed as a method to manage these metabolic diseases andmost frequently this is undertaken by using probiotics, prebiotics or synbiotics. Furthermore, the action ofmetformin, the most commonly prescribed drug for treating T2DM, is mediated in part by the gut microbiota,although this interplay may also be responsible for the frequent gastrointestinal adverse effects of metformin.Thus, adding a gut microbiota modulator (GMM), such as probiotics or prebiotics, to metformin therapy couldamplify its anti-diabetic effects, while decreasing its adverse reactions. This review summarizes the varioustherapies that are used to shift the composition of the microbiome and their efficacy in alleviating metabolicparameters, it assesses the interaction between metformin and the gut microbiota, and it evaluates the existingclinical and preclinical studies that analyze the potential synergy of a combined metformin-GMM therapy.