Objective: This study investigated the association between brain-derived neurotrophic factor (BDNF) gene polymorphisms and antidepressant response in patients with first-episode late-life depression (LLD). Methods: A total of 72 patients with first-episode LLD were recruited and 57 completed an 8-week course of antidepressant treatment. Participants were assessed at baseline and post-treatment using the 17-item Hamilton Depression Rating Scale (HAMD-17) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Serum BDNF levels were measured via Enzyme-Linked Immunosorbent Assay (ELISA) and BDNF gene polymorphisms were genotyped using the Agena® MassARRAY system. Results: After 8 weeks, 17 of the 57 patients with LLD showed effective treatment response (effective group), while 40 were classified as ineffective. Significant post-treatment improvements were observed across the cohort in HAMD-17 and RBANS scores, and serum BDNF levels compared with baseline (p < 0.05). However, the effective and ineffective groups did not have significantly different RBANS scores or serum BDNF levels (p > 0.05). Binary logistic regression identified male sex (OR = 10.094, p = 0.007) and BDNF gene polymorphism (OR = 6.559, p = 0.003) as predictors of treatment efficacy. Conclusion: Antidepressant treatment for 8 weeks altered serum BDNF levels in patients with LLD, with male patients carrying the Val/Val genotype potentially responded better to conventional antidepressants. The small sample size may limit the generalizability of these findings. Clinical Trial Registration: The study was registered at https://www.chictr.org.cn (registration number: ChiCTR1900024445).