Background Major depressive disorder (MDD) is a heterogeneous condition featured with a continuous low mood, feeling of sadness, lack of interest to perform daily activities. Genetic, physiological, biological, social, and environmental factors are associated with the pathophysiology of depression. Though several human studies failed to identify the suitable biological markers for depression, some animal studies showed phospholipids play a vital role in the alteration of emotion. Thus, the current study aimed to measure the serum levels of lysophosphatidic acid (LPA) and lysophosphatidylcholine (LPC) in MDD patients and healthy controls (HCs) to explore their roles and relationship with depression. Methods This case-control study enrolled 53 MDD patients and 50 HCs matched by age, gender, and body mass index. Based on the diagnostic and statistical manual of mental disorders, 5 th edition, a qualified psychiatrist diagnosed patients and assessed HCs. We applied the Hamilton depression rating scale (Ham-D) to measure the severity of depression. We used enzyme-linked immunosorbent assay kits to measure serum lysophosphatidic acid and lysophosphatidylcholine levels. Results We found no alterations of these parameters in serum levels of MDD patients compared to HCs. We also observed a significant positive correlation between LPA and LPC levels in MDD patients. Moreover, the present study showed no significant associations between target markers and either diagnosis of depression or Ham-D scores, or management of depression. Conclusion The present study suggests that LPA and LPC levels probably would not serve as potential biomarkers of MDD. Thus, we recommend further studies with large and more homogeneous populations to explore the exact relationship between serum lipids and MDD.