Objective To explore the effect of venlafaxine combined with agomelatine on the efficacy of senile depression and the effect of serum brain-derived neurotrophic factor （BDNF）. Methods A total of 104 elderly patients with depression admitted to Guanyuan Mental Health Center from October 2019 to November 2020 were selected as the research objects， and they were divided into study group （52 cases） and control group （52 cases） by a random number table. The control group was treated with agomelatine combined with placebo， and the study group was treated with venlafaxine combined with agomelatine. The scores of Hamilton Depression Scale （HAMD）， clinical efficacy， BDNF， S100β and cognitive function were compared between the two groups before and after treatment. The drug safety of the two groups were recorded. Results The HAMD scores of the control group after 4 weeks of treatment and after 12 weeks of treatment were （15.58±3.01） points and （11.37±2.13） points respectively， and the study group were （12.11±2.34） points and （9.23±1.57） points respectively， which were all lower than those before treatment （P＜ 0.05）. HAMD scores of the two groups after 12 weeks of treatment were lower than those after 4 weeks of treatment （P＜ 0.05）. HAMD scores of the study group after 4 weeks and after 12 weeks of treatment were lower than those of the control group （P＜ 0.05）. The total effective rate of the study group （92.31%，48/52） was higher than that of the control group （76.92%，40/52） （P ＜ 0.05）. The S100β of the control group after 4 weeks of treatment and after 12 weeks of treatment were （1.81±0.32） μg/L and （1.41±0.25） μg/L， study group were （1.52±0.28） μg/L and （1.19±0.18） μg/L， which were lower than those before treatment （P ＜ 0.05）. S100β after 12 weeks of treatment in two groups was lower than that after 4 weeks of treatment （P ＜ 0.05）. The BDNF of the control group after 4 weeks of treatment and after 12 weeks of treatment were （29.18±5.46） μg/L and （43.52±8.24） μg/L， and the study group were （33.43±6.17） μg/L and （47.49±7.83） μg/L， which were higher than those before treatment （P ＜ 0.05）. BDNF after 12 weeks of treatment in both groups was higher than that after 4 weeks of treatment （P ＜ 0.05）. The S100β of the study group after 4 weeks of treatment and 12 weeks of treatment were lower than that of the control group （P ＜ 0.05）， and BDNF was higher than that of the control group （P ＜ 0.05）. The score of the Repetitive Neuropsychological State Test （RBANS） after 12 weeks of treatment in the control group was （78.28±10.23） points， the study group was （82.09 ±11.76） points， which were both higher than those before treatment and 4 weeks after treatment （P ＜ 0.05）. The RBANS score of the study group after 12 weeks of treatment was higher than that of the control group （P ＜ 0.05）. There was no significant difference in the incidence of total adverse drug reactions between the two groups （P ＞ 0.05）. Conclusions Venlafaxine combined with agomelatine can significantly reduce the score of depression symptoms in elderly depression patients， enhance the efficacy， improve neurological function and cognitive function， and has good safety.