Objective: To investigate the protective effect of dexmedetomidine combined with lidocaine on brain in patients undergoing craniocerebral tumor surgery. Methods: 60 patients with craniocerebral tumor surgery were divided into lidocaine group, dexmedetomidine group and combined group according to different anesthesia schemes, 20 cases in each group. Rocuronium bromide, sufentanil, propofol and midazolam were used for anesthesia induction. Dexmedetomidine group was given continuous infusion of 0.4 μg·kg-1·h-1 dexmedetomidine during anesthesia maintenance. Lidocaine group was given continuous infusion of 2.0 mg·kg- 1·h-1 lidocaine during anesthesia maintenance. Dexmedetomidine 0.2 μg·kg-1·h-1 and lidocaine 1.0 mg·kg-1·h-1 were continuously infused during anesthesia maintenance in the combined group.The levels of serum neuron-specific enolase (NSE), S-100β, inflammatory factors, cognitive function and neurological function were measured. Results: There was no significant difference in serum NSE and S-100β levels among the three groups before administration (T0) (P>0.05). At T1, T2 and T3, the serum NSE and S-100β levels in the lidocaine group were lower than those in the dexmedetomidine group (P<0.05), and the combined group was lower than the lidocaine group (P<0.05). There was no significant difference in the levels of IL-6, TNF-α, hs-CRP and NFA score among the three groups before operation (P>0.05). The levels of IL-6, TNF-α, hs- CRP and NFA score in the lidocaine group were lower than those in the dexmedetomidine group (P<0.05), and those in the combined group were lower than those in the lidocaine group (P<0.05). There was no significant difference in MMSE score among the three groups before operation (P>0.05). After operation, the MMSE score of the lidocaine group was higher than that of the dexmedetomidine group (P<0.05), and the combined group was higher than the lidocaine group (P<0.05). Conclusion: Lidocaine combined with dexmedetomidine can significantly reduce the levels of nerve injury markers and inflammatory factors in craniocerebral tumor surgery, improve postoperative cognitive function and neurological function, and have potential advantages in brain protection.