Background <p>Rhino-orbito-cerebral mucormycosis, caused by pathogens such as <i>Rhizopus delemar</i>, is a life-threatening opportunistic infection primarily affecting immunosuppressed individuals. Anti-melanoma differentiation-associated protein 5-positive dermatomyositis (MDA5⁺ DM) is a distinct subtype of DM associated with interstitial lung disease (ILD) and high mortality. Fungal co-infections in anti-MDA5⁺ DM, particularly mucormycosis, are rarely reported.</p> Case presentation <p>We report a case of rhino-orbito-cerebral mucormycosis caused by <i>Rhizopus delemar</i> in a patient with anti-MDA5⁺ DM. The patient was receiving high-dose glucocorticoids and immunosuppressive therapy for rapidly progressive ILD, and later she developed progressive neurological symptoms, palatal ulceration with black eschar, and periorbital swelling. Metagenomic next-generation sequencing (mNGS) of blood subsequently identified <i>Rhizopus delemar</i>, and the diagnosis was further supported by cerebrospinal fluid mNGS. Antifungal therapy was adjusted promptly after pathogen identification. Despite aggressive treatment, the infection progressed rapidly with central nervous system involvement.</p> Conclusions <p>This case highlights the heightened susceptibility to invasive mucormycosis in patients with anti-MDA5⁺ DM, likely exacerbated by immunosuppressive therapy. Early diagnosis using mNGS and prompt initiation of targeted antifungal therapy are critical in managing such co-infections. Clinicians should maintain a high index of suspicion for invasive fungal infections in immunosuppressed anti-MDA5⁺ DM patients presenting with non-specific neurological or sinus symptoms.</p>