N-methyl-D-aspartate receptor (NMDA-R) antibody encephalitis is an immune-mediated disorder characterized by the presence of anti-NMDA antibody in serum and cerebrospinal fluid, with a characteristic combination of psychological and neurological signs and symptoms. The scientific knowledge pertaining to the management of anti-NMDA-R encephalitis is growing. It is important that neuroscience nurses be aware of treatments as well as the newest novel treatment options available. Early aggressive intervention is imperative to recovery. The first line of treatment often includes high-dose steroids, intravenous immunoglobulin, and therapeutic plasma exchange. Second-line therapy for refractory NMDA-R encephalitis includes intravenous rituximab and cyclophosphamide. Even with these treatments, up to 25% of patients may be left with severe deficits or have a fatal outcome. It is well known that penetration of monoclonal anti-CD20 antibody therapy (rituximab) into the cerebrospinal fluid is 0.1% of that in the serum. Therefore, efficacy of rituximab in the treatment of NMDA encephalitis may be improved by intrathecal administration in selected cases with a poor response to intravenous rituximab. We present a case of anti-NMDA-R encephalitis that was refractory to first- and second-line therapies, who responded to intrathecal rituximab, to highlight a novel treatment that may be able to prevent long-term disability and improve clinical outcomes.