A 42-year-old woman with relapsing systemic lupus erythematosus (SLE) complicated by Rowell's syndrome and recently diagnosed moyamoya disease presented with new onset weakness of the lower extremities. Laboratory tests showed serology for active lupus, and magnetic resonance imaging (MRA) confirmed worsening moyamoy syndrome with suspected central nervous system lupus. Anifrolumab was discontinued and pulsed corticosteroids and rituximab were started, resulting in marked neurological improvement. Rowell syndrome flared later, so anifrolumab was reintroduced during rituximab. This dual biologic treatment produced significant clinical improvement in skin symptoms. This is the first described case of successful treatment of refractory SLE with skin and neurological involvement with a combination of rituximab and anifrolumab.