Objective To explore the changes of serum homocysteine（ Hcy）， brain-derived neurotrophic factor（ BDNF） and neuregulin-1（ NRG-1）， and their relationship with cognitive impairment in elderly depression patients. Methods A total of 116 elderly patients with depression who were treated in Xuzhou Oriental People's Hospital from January 2016 to June 2019 were enrolled as the observation group. According to scoring results of Mini-Mental State Examination（ MMSE）， 57 patients with cognitive impairment and 59 patients without cognitive impairment in the observation group were enrolled as cognitive impairment group and cognitive non-impairment group. A total of 100 healthy people in the same period were enrolled as control group. The changes of serum Hcy， BDNF NRG-1 were compared among all groups， so as to explore the relationship between their changes and cognitive impairment. Results Hcy of cognitive impairment group was （29.49±6.36） μmol/L， which was higher than（ 10.47±3.31） μmol/L of control group and（ 15.58±4.27） μmol/L of cognitive non-impairment group. BDNF of cognitive impairment group was（ 6.57±1.58） μg/L， which was lower than（ 18.26±4.73） μg/L of control group and（ 13.24±3.45） μg/L of cognitive non-impairment group. The level of NRG-1 of cognitive impairment group was（ 11.25±4.12） pg/ml， which was lower than（ 32.50±7.14） pg/ml of control group and（ 23.38±5.26） pg/ml of cognitive non-impairment group. MMSE score of cognitive impairment group was（ 21.36±1.05）， which was lower than（ 28.01±0.94） of control group and（ 27.93±0.71） of cognitive non-impairment group. Compared with the control group， Hcy increased， while BDNF and NRG-1 levels decreased in cognitive non-impairment group（ P ＜ 0.05）. MMSE score was negatively correlated with serum Hcy， and positively correlated with BDNF and NRG-1 levels in the observation group（ r=-0.790，0.778，0.777； P ＜ 0.05）. When predicting cognitive impairment in elderly patients with depression， AUC of Hcy combined with BDNF and NRG-1 had a greatest value 0.884， which was better than each of them alone（ P ＜ 0.05）. Univariate analysis showed that Hcy level and the number of patients living alone in cognitive impairment group were higher than those in cognitive non-impairment group， while levels of BDNF and NRG-1 were lower than those in cognitive non-impairment group（ P＜ 0.05）. Multivariate analysis showed that Hcy（ OR=3.688）， BDNF（ OR=2.575）， NRG-1 （OR=3.019） and living alone（ OR=1.388） were independent risk factors of cognitive impairment in elderly patients with depression（ P＜0.05）. Conclusions The serum Hcy in elderly depression patients with cognitive impairment is higher than that in healthy people and those without cognitive impairment， while levels of BDNF and NRG-1 are lower. Clinical detection of serum Hcy， BDNF and NRG-1 levels in elderly patients with depression can effectively predict the possibility of cognitive impairment， so as to conduct early prevention and improve their quality of life.