Objective To investigate the effects of levetiracetam combined with sodium valproate on negative emotions and serological indexes in patients with epilepsy. Methods A total of 78 patients with epilepsy admitted to Oriental People"s Hospital of Luoyang were included in this study. All patients were divided into control group (39 cases, valproate sodium treatment) and study group (39 cases, levetiracetam combined with valproate sodium treatment) according to different treatment methods, and were treated for 3 months. Clinical indexes, negative emotion scores, serological indexes before and after treatment and adverse reactions were compared between the two groups . Results After treatment, the frequency and duration of seizures in 2 groups were improved compared with that before treatment, and the study group was significantly improved (t=20.328, 9.446, P<0.05). At 3 months after treatment, the negative emotion scores of both groups were improved compared with those before treatment, and the study group was significantly improved (t=12.084, 13.685, both P<0.05). At 3 months after treatment, the levels of neuronal specific enolase (NSE) indexes in both groups were lower than before treatment, and lower in study group, while the levels of dopamine (DA) and 5-hydroxytryptamine (5-HT) indexes were higher than before treatment, and higher in study group (t=7.057, 3.826, 4.763, all P<0.05). There was no significant difference in the total incidence of adverse reactions between the two groups (χ2=0.092, P>0.05). . Conclusion In the treatment of epilepsy patients, the combination of the above two drugs can reduce the seizure frequency, shorten the seizure duration, relieve anxiety and depression, and improve the level of serum neurotransmitter indexes, with good safety.