Methamphetamine use can induce psychosis resembling acute schizophrenia spectrum psychosis, making it challenging to differentiate between the two based on symptoms alone. Brain-derived neurotrophic factor (BDNF) exerts a critical role in hippocampal neural plasticity, influencing critical cognitive functions such as memory and learning. This study aimed to determine the role of serum BDNF levels in schizophrenia and methamphetamine addiction. A case-control study was conducted involving 50 patients with schizophrenia, 50 patients with methamphetamine addiction, and 50 healthy control subjects recruited from Ibn-Rushed Psychiatric Teaching Hospital in Baghdad. Cognitive impairment was assessed using the Mini-Mental State Examination (MMSE), while serum BDNF levels were measured using ELISA following standardized protocols. The findings revealed significantly lower median levels of BDNF (0.36 pg/ml) in patients with schizophrenia compared to both the control group (0.51 pg/ml) and the methamphetamine group (0.72 pg/ml). Moreover, there was a significant difference observed between the methamphetamine group and the control group. At a cut-off value of BDNF=0.37 pg/ml, the sensitivity and specificity of BDNF in differentiating between schizophrenia and methamphetamine addiction were 84% and 70%, respectively. Serum level of BDNF could be used to differentiate between schizophrenia and methamphetamine addiction when clinical distinctions are challenging to detect.