Over the past few decades, clinicians and experts applied kinds of therapies for patients with malignant gliomas such as chemotherapy, radiation or surgical extraction. However, they used to ignore the real seriousness of neuropsychiatric symptoms after glioma, including cognitive dysfunction, anxiety, and depression, which severely impeded patients' recovery and prognosis. Interestingly, one of our previous clinical studies have found some behavioral symptoms in glioma patients were associated with systemic inflammation. Notopterol is one of the principal extracts of the traditional Chinese medicinal herb Notopterygium incisum having anti-tumour and anti-inflammatory activity. However, whether notopterol is beneficial to the treatment of glioma has not been reported. In this study, we found that notopterol inhibited growth and increased apoptosis of glioma via inhibiting STAT3 activity. In addition, notopterol treatment improved cognitive impairment and depression-like behavior in GL261 cell-based glioma mice via preventing the loss of dendritic spines and the reduction of synapse related proteins (PSD95 and Synapsin-1) in hippocampal neurons. Notopterol significantly reduced the levels of cytokines (iNOS, TNF-α, IL-6, and IL-β) and the activity of STAT3/NF-kB signalling pathway in peritumoural brain tissues and GL261 conditioned medium (GCM) treated microglial cell line (BV2 cells). These results demonstrated that notopterol not only exerted anti-glioma effects via inhibiting STAT3 activity, but improved neuropsychiatric symptoms via inhibiting tumour associated inflammation through modulation of the STAT3/NF-kB pathway in glioma-bearing mice.Copyright © 2023. Published by Elsevier B.V.