In the brain, the complement system plays a crucial role in the immune response and in synaptic elimination during normal development and disease. Here, we sought to identify pathways that modulate the production of complement component 4 (C4), recently associated with an increased risk of schizophrenia. To design a disease-relevant assay, we first developed a rapid and robust 3-D protocol capable of producing large numbers of immunocompetent astrocytes from pluripotent cells. Transcriptional profiling of these astrocytes confirmed the homogeneity of this population of dorsal fetal-like astrocytes. Next, using a novel ELISA-based small molecule screen to measure changes in the amount of C4 protein secreted from astrocytes, we found that certain epigenetic regulators, such as JQ1, a Bromodomain inhibitor, as well as inhibitors of intracellular signaling pathways such as NF-B and JAK/STAT, reduced basal C4 secretion and secretion observed in response to treating astrocytes with inflammatory stimuli. We then built a Connectivity Map (C4-CMap) to predict and validate additional key regulatory pathways, including one involving c-Jun-kinase (JNK). This work provides a foundation for developing therapies for CNS diseases involving the complement cascade.