Circulating levels of the astrocytic marker S100B have been associated with risk of neuropsychiatric or neurological disorders. However, reported effects have been inconsistent, and no causal relations have yet been established. We applied two-sample Mendelian Randomization (MR) on the association statistics from genome-wide association studies (GWAS) for circulating S100B levels measured 5-7 days after birth (the iPSYCH sample) and in an older adult sample (mean age, 72.5 years; the Lothian sample), upon those derived from major depression disorder (MDD), schizophrenia (SCZ), bipolar disorder (BIP), autism spectral disorder (ASD), Alzheimer’s disease (AD), and Parkinson’s disease (PD). We studied the causal relations in the two S100B datasets for risk of these six neuropsychiatric disorders. MR suggested increased S100B levels 5-7 days after birth to causally increase the risk of MDD (OR = 1.014; 95%CI = 1.007–1.022; FDR-correctedp= 6.43×10−4). In older adults, MR suggested increased S100B levels to have a causal relation to the risk of BIP (OR = 1.075; 95%CI = 1.026–1.127; FDR-correctedp= 1.35×10−2). No significant causal relations were found for the other five disorders. We did not observe any evidence for reverse causality of these neuropsychiatric or neurological disorders on altered S100B levels. Sensitivity analyses using more stringent SNP-selection criteria and three alternative MR models suggested the results are robust. Altogether, our findings imply a small cause-effect relation for the previously reported associations of S100B and mood disorders. Such findings may provide a novel avenue for the diagnosis and management of disorders.