The electromagnetic pulse (EMP) is a widespread electromagnetic disturbance that can disrupt electronic systems and pose health risks to personnel in operational areas. The biological effects of EMP radiation, especially on the central nervous system (CNS), are not yet fully understood but are gaining attention. This study examines the impact of EMP on the CNS using microglial cells as a model system. We found that mice exposed to a field strength of 600 kV/m with 1000 pulses per day for two weeks exhibited increased levels of oxidative stress. This exposure induced a microglia polarization to the M1 state, leading to neuroinflammation and disruption of the blood-brain barrier (BBB) by the pro-inflammatory response of microglia. Further analysis revealed that the NLRP3 inflammasome/NF-κB signaling pathway modulates the pro-inflammatory mechanisms of EMP irradiation. In conclusion, our findings show that EMP irradiation triggers neuroinflammation and BBB damage via NLRP3 inflammasome/NF-κB activation. This research highlights the effects of EMP radiation on the CNS and offers valuable insights into the potential targets for biomedical protection against it.