Clinical and experimental data indicate that spinal cord injury (SCI) elicits pathological T‐cell responses. Implicit in these data, but poorly understood, is that B lymphocytes (B cells) also contribute to the delayed pathophysiology of spinal trauma. Here, for the first time, we show that experimental spinal contusion injury elicits chronic systemic and intraspinal B cell activation with the emergence of a B cell‐dependent organ‐specific and systemic autoimmune response. Specifically, using sera from spinal cord injured mice, immunoblots reveal oligoclonal IgG reactivity against multiple CNS proteins. We also show SCI‐induced synthesis of autoantibodies that bind nuclear antigens including DNA and RNA. Elevated levels of anti‐DNA antibodies are a distinguishing feature of systemic lupus erythematosus and, via their ability to cross‐react with neuronal antigens, can cause neuropathology. We show a similar pathologic potential for the autoantibodies produced after SCI. Thus, mammalian SCI produces marked dysregulation of B cell function (i.e. autoimmunity) with pathological potential.