Adverse drug reactions are critical considerations in managing complex medical conditions. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but potentially life-threatening hypersensitivity reaction characterized by rash, eosinophilia, and multisystem involvement. Daptomycin, an antibiotic commonly used for resistant Gram-positive infections, has been associated with both eosinophilic pneumonia and DRESS syndrome. Challenges in diagnosing daptomycin-induced eosinophilic pneumonia arise due to overlapping symptoms with infectious or inflammatory processes, further complicated by concurrent COVID-19 infection. This case highlights a patient with acute hypoxemic respiratory failure (AHRF) attributed to DRESS syndrome caused by daptomycin, underscoring the diagnostic challenges and therapeutic considerations in such scenarios.