Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect almost every organ. Lupus protein-losing enteropathy (PLE) is one of the rarest manifestations of gastrointestinal involvement. Lupus flare as initial presentation is rare and the disease can act as a trigger to other pathologic immune syndromes like Hemophagocytic Lymphohistiocytosis (HLH), although this association is rare. We report the case of a previously healthy African 39-year-old female patient, with a recent history of cesarean section. Admitted to the Emergency Department (ED) with diffuse abdominal pain and fever, having completed a cycle of antibiotic therapy for initially suspected endometritis. The clinical picture progressed with sustained high fever, new-onset lymphadenopathies, systemic rash, acute pulmonary edema and seizures. Laboratory findings included hyperferritinemia, hypertriglyceridemia, proteinuria and hypoalbuminemia. The auto-immune panel was positive for antinuclear antibodies (ANA), anti-dsDNA, anti-SSA and anti-SSB, anti-PL7, anti-RNP, anti-U1-SnRNP, and anti-Pm-Scl75. She also presented hypocomplementemia. An inaugural flare of SLE with multisystemic involvement and concomitant secondary Hemophagocytic Syndrome was considered and therapy with methylprednisolone pulses, Anakinra and Cyclophosphamide was started. By the end of the first cycle of cyclophosphamide, the patient presented clinical worsening with abdominal pain recrudescence and profuse diarrhea. After the exclusion of an infectious process, a Lupus PLE was assumed and Cyclophosphamide protocol was resumed, with sustained clinical improvement after the induction protocol. Despite initially suspected gynecological infection, the clinical progression with multisystemic involvement together with the auto-immune panel made the diagnosis of SLE possible, with other laboratory findings raising the suspicion of HLH. This case represents a rare report of severe SLE with multiple organ involvement accompanied by HLH. Gastrointestinal involvement with PLE added rarity and morbidity to the clinical picture. The case reinforces the idea that when organ dysfunction is due to a severe autoimmune response, supportive treatment can be lifesaving until immunosuppressive drugs reach their full effect.