Abstract Objectives This study aimed to explore the effect of antidepressant treatment on the HPA axis, changes in depression score, and serum levels of TNF-α in depressed infertile women. Methods In this randomized controlled trial research, 60 infertile women who had undergone in vitro fertilization (IVF) treatment with depression scores between 16-47 were divided into two groups. The intervention group with fluoxetine capsule was under treatment for two months before the embryo transfer, while the control group was given placebo. Depression score, serum levels of tumor necrosis factor alpha (TNF-α) as well as cortisol hormone levels were measured and recorded both before and after the intervention. The data were analyzed using SPSS version 21 software. Results We analyzed the data related to 55 subjects who had undergone embryo transfer. 7 subjects in the intervention group and 3 in the control group got pregnant. We observed a significant decrease in the depression score (p < 0/001) and serum levels of cortisol (p = 0/001) in the intervention group. There was a significant increase in the serum levels of TNF-α in the intervention group (p < 0/001). There was a significant difference between the two groups in the number of pregnancies (p = 0.04). However, there was no statistical difference between them with regard to the number of harvested oocytes (p = 0.174). Discussion Decrease in depression score and cortisol level, and an increase in the levels of TNF-α in the intervention group caused any changes in the number of oocytes in comparison with the control group. However, the number of pregnancies was larger in the intervention group.