Mechanistically, both treatments inhibited the activation of the MAPK/P65/NLRP3 pathway in hippocampal microglia and LPS-stimulated BV2 cells.<h4>Conclusion</h4>Our findings demonstrate that melatonin mitigates asthma-related airway inflammation and neuropsychiatric comorbidity by modulating the gut microbiota-SCFA axis and suppressing microglial activation via the MAPK/P65/NLRP3 pathway. Here, NLRP3 is linked to asthma.