Coccidioidomycosis, endemic in the southwestern United States, can lead to severe pulmonary complications, particularly in chronic obstructive pulmonary disease (COPD) patients with poor lung reserves. has a predisposition for structurally damaged lungs, commonly causing difficult-to-treat bronchiectasis and cavitary lesions. We present the case of a 58-year-old patient with advanced COPD and a remote history of pulmonary coccidioidomycosis diagnosed 30 years earlier, who was found to have sputum and radiographic evidence of cavitary lung disease 4 years prior to admission, but was lost to follow-up. The current presentation is attributed to the progression of untreated infection and reactivation of latent infection. Despite the initiation of antifungal and antibiotic therapy, the subsequent course was complicated by the development of bronchopleural fistula and worsening respiratory failure, leading to an unfavorable outcome. This case highlights the diagnostic challenges associated with overlapping clinical and radiologic features of concurrent infections and devastating outcomes in patients with COPD. Prompt diagnostic testing and prolonged comprehensive therapy are of paramount importance in managing such complex infections.