Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with unpredictable course and flares. The clinical manifestation can vary from mild to severe and life-threatening disease. Infection is the primary cause of mortality in hospitalized SLE patients. There is a paucity of evidence to support the co-management of SLE with major organ involvement and sepsis. We describe the clinical response of a 35-year-old male diagnosed with SLE; then, he developed severe sepsis and a flare of SLE with major organ involvement including lupus nephritis (LN), myocarditis, and neuropsychiatric systemic lupus erythematosus (NPSLE). Based on the patient's condition, a treatment dilemma was encountered, and after a multidisciplinary meeting, the decision was made to use a combination of rituximab (RTX), intravenous immunoglobulin (IVIG), and pulse steroid. Shortly, the patient's condition started to improve, and his symptoms were resolved. In conclusion, our clinical case suggests that combined RTX, IVIG, and pulse steroid seem to be effective and safe in achieving clinical response, thus representing a good choice for managing severe SLE flares in sepsis.