Microglia are highly plastic cells that can assume different phenotypes in response to microenvironmental signals. Lipopolysaccharide (LPS) and interferon‐γ (IFN‐γ) promote differentiation into classically activated M1‐like microglia, which produce high levels of pro‐inflammatory cytokines and nitric oxide and are thought to contribute to neurological damage in ischemic stroke and Alzheimer's disease. IL‐4 in contrast induces a phenotype associated with anti‐inflammatory effects and tissue repair. We here investigated whether these microglia subsets vary in their K⁺ channel expression by differentiating neonatal mouse microglia into M(LPS) and M(IL‐4) microglia and studying their K⁺ channel expression by whole‐cell patch‐clamp, quantitative PCR and immunohistochemistry. We identified three major types of K⁺ channels based on their biophysical and pharmacological fingerprints: a use‐dependent, outwardly rectifying current sensitive to the K_V1.3 blockers PAP‐1 and ShK‐186, an inwardly rectifying Ba²⁺‐sensitive K_ir2.1 current, and a Ca²⁺‐activated, TRAM‐34‐sensitive K_Ca3.1 current. Both K_V1.3 and K_Ca3.1 blockers inhibited pro‐inflammatory cytokine production and iNOS and COX2 expression demonstrating that K_V1.3 and K_Ca3.1 play important roles in microglia activation. Following differentiation with LPS or a combination of LPS and IFN‐γ microglia exhibited high K_V1.3 current densities (∼50 pA/pF at 40 mV) and virtually no K_Ca3.1 and K_ir currents, while microglia differentiated with IL‐4 exhibited large K_ir2.1 currents (∼ 10 pA/pF at −120 mV). K_Ca3.1 currents were generally low but moderately increased following stimulation with IFN‐γ or ATP (∼10 pS/pF). This differential K⁺ channel expression pattern suggests that K_V1.3 and K_Ca3.1 inhibitors could be used to inhibit detrimental neuroinflammatory microglia functions. GLIA 2016;65:106–121