Here, we show that miR-669c-3p is induced upon brain ischemia, its intracerebral overexpression modulates microglial/macrophage activation and it directly targets the myeloid differentiation primary response gene 88 (MyD88), the canonical adaptor protein implicated in toll-like receptor (TLR) and IL-1 signaling, critical in mediating innate immune responses. Here, MYD88 is linked to brain ischemia.