The results of recent studies suggest that metformin, in addition to its antihyperglycemic efficacy, may also attenuate neuroinflammation and directly act on the central nervous system. However, the molecular mechanisms by which metformin exerts its anti-inflammatory effects in the brain remain largely unknown. Adenosine-monophosphate-activated protein kinase (AMPK) activation is the most well-known mechanism of metformin action. However, some of the biological responses to metformin (e.g. the release of cytokines and the expression of arginase I or PGC-1α) are not limited to AMPK activation but also are mediated by AMPK-independent mechanisms. This article reviews current evidence supporting the hypothesis that the shift of microglia toward alternative activation may underlie the beneficial effects of metformin observed in animal models of neurological disorders.