Metformin is a first-line oral antidiabetic agent that results in clear benefits in relation to glucose metabolism and diabetes-related complications. The specific regulatory details and mechanisms underlying these benefits are still unclear and require further investigation. There is recent mounting evidence that metformin has pleiotropic effects on the target tissue development in metabolic organs, including adipose tissue, the gastrointestinal tract and the liver. The mechanism of actions of metformin are divided into direct effects on target tissues and indirect effects via non-targeted tissues. MicroRNAs (miRNAs) are a class of endogenous, noncoding, negative gene regulators that have emerged as important regulators of a number of diseases, including type 2 diabetes mellitus (T2DM). Metformin is involved in many aspects of miRNA regulation, and metformin treatment in T2DM should be associated with other miRNA targets. A large number of miRNAs regulation by metformin in target tissues with either direct or indirect effects has gradually been revealed in the context of numerous diseases and has gradually received increasing attention. This paper thoroughly reviews the current knowledge about the role of miRNA networks in the tissue-specific direct and indirect effects of metformin. Furthermore, this knowledge provides a novel theoretical basis and suggests therapeutic targets for the clinical treatment of metformin and miRNA regulators in the prevention and treatment of cancer, cardiovascular disorders, diabetes and its complications.