Background: Antepartum depression is one of the leading causes of maternal morbidity and mortality in the prenatal period. There is accumulating evidence for the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of depression. The present study examines the extent to which maternal early pregnancy serum BDNF levels are associated with antepartum depression. Method: A total of 968 women were recruited and interviewed in early pregnancy. Antepartum depression prevalence and symptom severity were assessed using the Patient Health Questionnaire-9 (PHQ-9) scale. Maternal serum BDNF levels were measured using a competitive enzyme-linked immunosorbent assay (ELISA). Logistic regression procedures were performed to estimate odds ratios (OR) and 95% confidence intervals (95% CI) adjusted for confounders. Results: Maternal early pregnancy serum BDNF levels were significantly lower in women with antepartum depression compared to women without depression (mean ± standard deviation [SD]: 20.78 ± 5.97 vs. 21.85 ± 6.42 ng/ml, p = 0.024). Lower BDNF levels were associated with increased odds of maternal antepartum depression. After adjusting for confounding, women whose serum BDNF levels were in the lowest three quartiles (<17.32 ng/ml) had 1.61-fold increased odds (OR = 1.61, 95% CI: 1.13, 2.30) of antepartum depression as compared with women whose BDNF levels were in the highest quartile (>25.31 ng/ml). There was no evidence of an association of BDNF levels with depression symptom severity. Conclusions: Lower maternal serum BDNF levels in early pregnancy are associated with antepartum depression. These findings may point toward new therapeutic opportunities and BDNF should be assessed as a potential biomarker for risk prediction and monitoring response to treatment for antepartum depression.