Type 2 diabetes mellitus (T2DM) and T2DM-related complications [such as retinopathy, nephropathy, and cardiovascular diseases (CVDs)] are the most prevalent metabolic diseases. Intriguingly, overwhelming findings have shown a strong association of the gut microbiome with the etiology of these diseases, including the role of aberrant gut bacterial metabolites, increased intestinal permeability, and pathogenic immune function affecting host metabolism. Thus, deciphering the specific microbiota, metabolites, and the related mechanisms to T2DM-related complications by combined analyses of metagenomics and metabolomics data can lead to an innovative strategy for the treatment of these diseases. Accordingly, this review highlights the advanced knowledge about the characteristics of the gut microbiota in T2DM-related complications and how it can be associated with the pathogenesis of these diseases. Also, recent studies providing a new perspective on microbiota-targeted therapies are included.