Neuroleptic malignant syndrome (NMS) is a potentially fatal neurological emergency that occurs as an idiosyncratic reaction to antipsychotics. Human alpha-synuclein (α-syn) protein is a neuronal cytoskeleton-related protein that has been recently implicated in the development of chronic neurodegenerative disorders. This study was conducted to evaluate the correlation between serum levels of IgM and IgG anti-synuclein alpha (anti-SNCa) auto-antibodies and the risk of development of NMS in psychiatric patients administered antipsychotic medications, as well as to investigate the diagnostic value of these antibodies as potential biomarkers for diagnosis of antipsychotics-induced brain damage in psychiatric patients presenting with NMS. The study was carried out on 150 subjects, divided into three groups: group I (case group) included 30 psychiatric patients presenting with NMS, group II (positive control group) included 60 psychiatric patients on antipsychotic medications with no previous history of NMS, and group III (negative control group) included 60 normal healthy volunteers. Serum levels of IgM and IgG antibodies were measured using ELIZA. This study revealed that the median serum levels of both IgM and IgG anti-SNCa antibodies were significantly higher in the case group, when compared with the two control groups (p < 0.001). Significant associations were identified between increasing serum levels of IgM and IgG anti-SNCa antibodies, chronic antipsychotic drug intake, and development of NMS among psychiatric patients, and that these antibodies can be used as predictor biomarkers for brain damage, with high sensitivity and specificity, in psychiatric patients presenting with NMS.