Fermented Gastrodia elata (FGE) attenuates methamphetamine (METH)-induced hippocampal neuroinflammation and anxiety- and depression-like behavior in mice. The study created a mouse model with METH-induced anxiety and depressive behavior, accompanied by hippocampal neuron pathology, activation of astrocytes and microglia. FGE significantly ameliorated pathological changes in the hippocampus, reduced glial cell activation, and alleviated anxious and depressive-like behaviors as demonstrated by behavioral tests. Network pharmacology, ELISA and RT-PCR confirmed the role of the PI3K-AKT signaling pathway in the neuroprotective effects of FGE. Active components of FGE, such as GABA and 4-HBA, contribute to anti-inflammatory and neuroprotective properties. The findings suggest FGE as a promising agent against METH-related neurological disorders.