Obesity is a systemic disease and represents one of the leading causes of death worldwide by constituting the 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 and obesity but are difficult to maintain by most patients. However, the recent focus on the intestinal microbiota and its important role in the host's metabolism provides a new key for improving metabolic health. Modulating the composition of the gut microbiota was proposed as a method to manage these metabolic diseases and most frequently this is undertaken by using probiotics, prebiotics or synbiotics. Furthermore, the action of metformin, 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 could amplify its anti-diabetic effects, while decreasing its adverse reactions. This review summarizes the various therapies that are used to shift the composition of the microbiome and their efficacy in alleviating metabolic parameters, it assesses the interaction between metformin and the gut microbiota, and it evaluates the existing clinical and preclinical studies that analyze the potential synergy of a combined metformin-GMM therapy.