Initially, children were thought to be spared from disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a month into the epidemic, a novel multisystem inflammatory syndrome in children (MIS-C) emerged. Herein, we report on the immune profiles of nine MIS-C cases. All MIS-C patients had evidence of prior SARS-CoV-2 exposure, mounting an antibody response with intact neutralization capability. Cytokine profiling identified elevated signatures of inflammation (IL-18 and IL-6), lymphocytic and myeloid chemotaxis and activation (CCL3, CCL4, and CDCP1), and mucosal immune dysregulation (IL-17A, CCL20, and CCL28). Immunophenotyping of peripheral blood revealed reductions of non-classical monocytes, and subsets of NK and T lymphocytes, suggesting extravasation to affected tissues. Finally, profiling the autoantigen reactivity of MIS-C plasma revealed both known disease-associated autoantibodies (anti-La) and novel candidates that recognize endothelial, gastrointestinal, and immune-cell antigens. All patients were treated with anti-IL-6R antibody and/or IVIG, which led to rapid disease resolution. Display omitted •The MIS-C anti-SARS-CoV-2 antibody repertoire resembles a convalescent response•Cytokine profiling indicates myeloid cell chemotaxis and mucosal inflammation•Mass cytometry uncovers immune cell activation and egress to the periphery•MIS-C autoantibodies target organ systems central to MIS-C pathology Insights into the cellular and serological immune dysfunction underlying MIS-C, a novel pediatric inflammatory syndrome associated with SARS-CoV-2 infection, reveal potential autoantibodies that may link organ systems relevant to pathology.