Abstract Background: Disturbances in structural and synaptic plasticity have been linked to depression and suicidal ideation. One of the major neurotrophic factors, the brain-derived neurotrophic factor (BDNF), is involved in the maintenance and survival of neurons and synaptic plasticity. This case–control study assesses the serum BDNF and suicidal ideation among drug-naïve and drug-treated MDD patients attending university hospitals and comparing them to healthy control. A simple random sample of 57 MDD patients and 57 age- and sex-comparable controls were enrolled. The researchers conducted a semi-structured interview to collect the demographic characteristics and disease history. Structured Clinical Interview for DSM-5 (SCID-5), Hamilton Depression Rating Scale (HDRS), and Beck Scale for Suicidal Ideation (BSS) were applied to the participants. Blood samples were collected to measure plasma BDNF level. Results: The MDD group had lower BDNF than the control group. Within the MDD group, drug-naïve patients had significantly lower BDNF than drug-treated patients. Female patients had lower BDNF than male patients. Positive family history of MDD was associated with low BDNF. Severe and moderate cases had lower BDNF than mild cases. High BSS (≥24) was associated with low BDNF. A statistically significant positive correlation was found between BDNF and age, disease duration, duration of the current episode, and the number of previous episodes. On the other hand, a statistically significant negative correlation was found between BDNF and age of MDD onset, HDRS, and BSS. A regression model was highly statistically significant in the prediction of HDRS. BDNF and disease duration were negatively correlated with HDRS. On the other hand, depression treatment status was not significantly associated with the HDRS prediction model. Conclusion: Our findings extend the neurotrophic concept of depression by identifying the decreased BDNF levels as a peripheral biomarker of MDD. Our assessment of depression and suicidal ideation (SI) and their relationship to decreased BDNF levels shed light on the etiopathology of MDD and its related suicidality. They should be more studied to understand better the mechanisms by which they develop. To further explore the effect of BDNF in suicide, larger study sizes and a range of psychiatric diagnoses associated with suicide attempts are required.