Neuroinflammatory responses to neurotoxic manganese (Mn) in CNS have been associated with the Mn-induced Parkinson-like syndromes. However, the framework of molecular mechanisms contributing to manganism is still unclear. Using an in vitro neuroinflammation model based on the insulated signaling pathway reporter transposon constructs stably transfected into a murine BV-2 microglia line, we tested effects of manganese (II) together with a set of 12 metal salts on the transcriptional activities of the NF-κB, activator protein-1 (AP-1), signal transducer and activator of transcription 1 (STAT1), STAT1/STAT2, STAT3, Nrf2, and metal-responsive transcription factor-1 (MTF-1) via luciferase assay, while concatenated destabilized green fluorescent protein expression provided for simultaneous evaluation of cellular viability. This experiment revealed specific and strong responses to manganese (II) in reporters of the type I and type II interferon-induced signaling pathways, while weaker activation of the NF-κB in the microglia was detected upon treatment of cells with Mn(II) and Ba(II). There was a similarity between Mn(II) and interferon-γ in the temporal STAT1 activation profile and in their antagonism to bacterial LPS. Sixty-four natural and synthetic flavonoids differentially affected both cytotoxicity and the pro-inflammatory activity of Mn (II) in the microglia. Whereas flavan-3-ols, flavanones, flavones, and flavonols were cytoprotective, isoflavones enhanced the cytotoxicity of Mn(II). Furthermore, about half of the tested flavonoids at 10–50 μM could attenuate both basal and 100–200 μM Mn(II)-induced activity at the gamma-interferon activated DNA sequence (GAS) in the cells, suggesting no critical roles for the metal chelation or antioxidant activity in the protective potential of flavonoids against manganese in microglia. In summary, results of the study identified Mn as a specific elicitor of the interferon-dependent pathways that can be mitigated by dietary polyphenols.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12035-023-03369-w.