Acting as immune cells, microglia play a surveillance role in central nervous system injuries and diseases. Extracellular nucleotides such as ATP and UTP, and adenosine are reported to regulate the response of microglia to insults and disease. ATP activates P2X receptors and triggers several signal cascades, resulting in the activation of microglia. Subsequently, UDP binding to the P2Y6 receptor induces phagocytosis by microglia, while adenosine regulates process retraction in microglia. Nucleotides and adenosine leak out from dead cells and act on their corresponding receptors on microglia, stimulating the release of inflammatory factors and cytokines to provide both neurotrophic and neurotoxic effects. In this article, we review the regulatory effects of nucleotides and adenosine on microglial chemotaxis, phagocytosis, and process retraction, and summarize the activities of these cells after ischemia.