Objective To investigate the association between the single nucleotide polymorphism （SNP） rs3924999 of neuregulin 1（ NRG1） and the SNP rs6265 of brain-derived neurotrophic factor（ BDNF） with susceptibility to and clinical symptoms of geriatric depressive disorder. Methods The case group consisted of 76 patients with first-episode geriatric depressive disorder recruited from the outpatient clinics and inpatients wards of Beijing Anding Hospital， Capital Medical University between February and December 2021. The control group comprised 37 healthy geriatric volunteers recruited from communities in the Beijing during the same period. Genetic polymorphism in the NRG1（ rs3924999） and BDNF（ rs6265） were analyzed in two groups， and the chi-square test was used to compare differences in genotype distribution between the groups. One-way analysis of variance（ ANOVA） was used to compare differences between genotypes within case group and scores of the 17-item Hamilton Depression Scale（ HAMD-17）， Hamilton Anxiety Scale（ HAMA）， 9-item Patient Health Questionnaire（ PHQ-9）， 7-item Generalized Anxiety Disorder（ GAD-7）， Mini-Mental State Examination（ MMSE）， Montreal Cognitive Assessment（ MoCA）， Insomnia Severity Index（ ISI）， and Activities of Daily Living Scale（ ADL）. Multiple comparisons were corrected using the Bonferroni method. Results There was a statistically significant difference in the distribution of the NRG1 rs3924999 genotype between the two groups（ χ2=7.123， P=0.028）； however， after correction for multiple comparisons using the Bonferroni method （corrected significance threshold P=0.025）， the difference was no statistically significant（ P＞0.05）. There was no statistically significant difference in the distribution of the BDNF rs6265 genotype between the two groups （χ2=0.369，P=0.831）. There were no statistically significant differences in clinical symptom scores or cognitive function scores among different genotypes（ AA， GA， GG） of the NRG1 rs3924999 in case group（ all P＞0.05）. There were statistically significant differences in MoCA scores among the different BDNF rs6265 genotypes （CC，TC，TT）（ F=3.355， P=0.040）. After multiple comparison correction using the Bonferroni method， the difference between the CC and TC genotypes was statistically significant［ mean difference=-3.179， 95%CI （-6.19， -0.17）， P=0.035］. Conclusions The polymorphism at the rs3924999 locus of the NRG1 gene may be associated with susceptibility to geriatric depressive disorder， while the polymorphism at the rs6265 locus of the BDNF gene may be associated with cognitive impairment in geriatric depressive disorder.