Neuropsychiatric disorders present a global health challenge, necessitating an understanding of their molecular mechanisms for therapeutic development. Using Mendelian randomization (MR) analysis, this study explored associations between genetically predicted levels of 173 proteins in cerebrospinal fluid (CSF) and 25 in the brain with 14 neuropsychiatric disorders and risk factors. Follow-up analyses assessed consistency across plasma protein levels and gene expression in various brain regions. Proteins were instrumented using tissue-specific genetic variants, and colocalization analysis confirmed unbiased gene variants. Consistent MR and colocalization evidence revealed that lower cortical expression of low-density lipoprotein receptor-related protein 8, coupled higher abundance in the CSF and plasma, associated with lower fluid intelligence scores and decreased bipolar disorder risk. Additionally, elevated apolipoprotein-E2 and hepatocyte growth factor-like protein in the CSF and brain were related to reduced leisure screen time and lower odds of physical activity, respectively. Furthermore, elevated CSF soluble tyrosine-protein kinase receptor 1 level increased liability to attention deficit hyperactivity disorder and schizophrenia alongside lower fluid intelligence scores. This research provides genetic evidence supporting novel tissue-specific proteomic targets for neuropsychiatric disorders and their risk factors. Further exploration is necessary to understand the underlying biological mechanisms and assess their potential for therapeutic intervention.