Pneumocystis jirovecii pneumonia (PJP) is a life-threatening opportunistic infection predominantly affecting immunocompromised patients. Trimethoprim–sulfamethoxazole (TMP–SMX) remains the standard therapy but is often limited by severe toxicity. Rezafungin, a next-generation echinocandin with a long half-life, has shown preclinical activity against Pneumocystis spp., but its use in humans remains largely unexplored. We report the case of a 67-year-old man with inflammatory bowel disease who developed severe PJP complicated by acute respiratory failure, septic shock, and multiorgan dysfunction following corticosteroid and biologic therapy. Standard TMP–SMX therapy was contraindicated due to renal impairment and pancytopenia. The patient received rezafungin via a compassionate-use programme, with serial monitoring of serum and bronchoalveolar β-D-glucan levels. Despite a partial biomarker response, the patient ultimately progressed to refractory acute respiratory distress syndrome and multiorgan failure. This case provides preliminary human data suggesting that rezafungin may offer a potential therapeutic option for PJP when standard treatment is contraindicated or poorly tolerated. Close clinical and biomarker monitoring is essential. Further clinical and experimental studies are warranted to determine its efficacy, optimal dosing, and safety in critically ill immunocompromised patients.