Immune checkpoint inhibitors (ICIs) are increasingly associated with a broad spectrum of immune-related adverse events (irAEs), including rheumatic manifestations. We report a case of ICI-associated sicca syndrome (ICI-S) mimicking Sjögren’s disease, with a brief literature review. The patient was a 70-year-old man with BRAF-mutated metastatic melanoma who developed inflammatory arthralgias followed by parotid and submandibular enlargement, severe xerostomia, and xerophthalmia, during pembrolizumab therapy. Treatment was withheld and low-dose glucocorticoids (GC) initiated, with rapid improvement of joint symptoms and gland swelling, although marked xerostomia persisted. The diagnostic work-up revealed elevated inflammatory markers and positive antinuclear antibodies (ANA), with negative anti-SSA/SSB. Salivary gland ultrasound showed grade 3 changes (OMERACT) and PET-CT confirmed bilateral sialadenitis. Minor salivary gland biopsy demonstrated T-cell–predominant lymphocytic infiltrate without CD20+ B cells, supporting an ICI-S rather than primary Sjögren’s disease. Pembrolizumab rechallenge triggered a flare of sialadenitis and arthritis, controlled with GC reintroduction plus hydroxychloroquine and supportive measures. This case provides educational insights into the diagnostic differentiation between ICI-S and primary Sjögren’s disease, supporting early recognition and appropriate management without compromising oncologic treatment.