Acute mediastinitis is a common infectious complication following heart transplant surgery. The etiology is typically bacterial, and the condition tends to have a favourable outcome with appropriate source control and antimicrobial treatment. Clinically, it often presents acutely, with early dehiscence of the surgical wound and systemic involvement, necessitating prompt surgical intervention. Fungal etiology is rare and usually associated with severely immunocompromised patients, conferring a dismal prognosis. Although most fungal infections are caused by Aspergillus fumigatus, the widespread use of azoles as prophylactic treatment has led to an increase in infections by unknown species and other azole-resistant fungi, posing a significant therapeutic challenge. We present the case of a 31-year-old heart transplant recipient who developed post-surgical mediastinitis due to Aspergillus calidoustus following a complicated postoperative course and humoral rejection. Despite appropriate antimicrobial therapy and source control, the infection progressed unfavourably.