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Advanced HIV infection is associated with profound immunosuppression, predisposing patients to opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP) and Mycobacterium avium complex (MAC). PJP can cause severe respiratory disease, including acute respiratory distress syndrome (ARDS), while disseminated MAC may contribute to systemic illness and pulmonary complications. Concurrent infection with both pathogens is uncommon but may precipitate severe pulmonary failure. A man in his 40s presented with unintentional weight loss, fatigue, oral thrush, and progressive dyspnea. On arrival, oxygen saturation was 86% on room air, requiring high-flow nasal cannula. Laboratory evaluation revealed profound immunosuppression (CD4 7 cells/mm³, HIV RNA 123,000 copies/mL) and elevated β-D-glucan (>700 pg/mL). Chest CT demonstrated diffuse bilateral ground-glass opacities. He was initially treated empirically with broad-spectrum antibiotics (piperacillin-tazobactam and linezolid) and subsequently started on trimethoprim-sulfamethoxazole and corticosteroids for PJP. Despite supportive measures, the patient's respiratory status deteriorated, requiring intubation. Sputum cultures grew MAC, prompting initiation of azithromycin, rifampin, and ethambutol. The patient developed disseminated intravascular coagulation, acute tubular necrosis requiring daily hemodialysis, and septic shock requiring dual vasopressors. He was not a candidate for ECMO due to multi-organ failure in the context of advanced AIDS, and his prognosis remained guarded. This case highlights the rapid progression and complexity of opportunistic infections in advanced AIDS. Extensive diagnostic evaluation, early recognition of co-infections, and aggressive multidisciplinary management are essential, though outcomes may remain poor in patients with profound immunosuppression and multi-organ failure.