Granulomatosis with polyangiitis (GPA) is a systemic vasculitis frequently associated with serum anti-neutrophil cytoplasmic antibodies (ANCAs), particularly anti-proteinase 3 (PR3). Multisystem involvement is typical, although disease onset with simultaneous manifestations affecting both the ocular and otorhinolaryngologic systems is rare and poorly reported in the literature. We describe a 65-year-old woman with renal impairment with microscopic hematuria and proteinuria and PR3-positive who developed bilateral otitis leading to sensorineural hearing loss and severe anterior scleritis, with a high suspicion of ANCA-associated vasculitis. Despite immunosuppression therapy, persistently elevated serum anti-PR3 levels in the absence of overt clinical activity prompted further diagnostic evaluation, which revealed previously unrecognized subglottic stenosis (SGS), confirmed by MRI, and fully resolved after anti-CD20 therapy. Concurrent involvement of the upper airways and ocular district as the initial presentation of GPA is unusual and may precede renal involvement by several months. Persistent elevation of PR3 levels in an apparent state of clinical remission may indicate ongoing active disease in other anatomical sites. The integration of laboratory tests, imaging studies, and multidisciplinary assessment is essential for early diagnosis and effective therapeutic management.