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Polo-like kinase 2 (PLK2) is a serine/threonine protein kinase associated with the regulation of synaptic plasticity and centriole duplication. We identify PLK2 as a crucial early response gene in lipopolysaccharide (LPS)-stimulated microglial cells. Knockdown or inhibition of PLK2 remarkably attenuates LPS-induced expression of pro-inflammatory factors in microglial cells by suppressing the IKKβ-NF-κB signaling pathway. We identify heat shock protein 90 alpha (HSP90α), a regulator of IKKβ activity, as a novel PLK2 substrate. Knockdown or pharmacological inhibition of HSP90α abolishes PLK2-mediated activation of NF-κB transcriptional activity and microglial inflammatory activation. Furthermore, phosphoproteomic analysis pinpoints Ser252 and Ser263 on HSP90α as novel phosphorylation targets of PLK2. Lastly, conditional knockout of PLK2 in microglial cells dramatically ameliorates neuroinflammation and subsequent dopaminergic neuron loss in an intracranial LPS-induced mouse PD model. The present study reveals that PLK2 promotes microglial activation through the phosphorylation of HSP90α and subsequent activation of the IKKβ-NF-κB signaling pathway.