A man in his 60s with multiple vascular comorbidities presented with sudden, painless vision loss in one eye. Although he had a high risk for atherosclerotic events, initial evaluation for stroke was negative for acute ischemia, but found to have markedly elevated inflammatory markers. Accordingly, giant cell arteritis was investigated and Ophthalmologic findings and fulfillment of the 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria supported the diagnosis of giant cell arteritis, despite a negative temporal artery biopsy. Management included high-dose glucocorticoids and delayed tocilizumab initiation due to the need for multiple vascular surgeries. Vision loss was irreversible, but systemic symptoms resolved and vascular interventions were successful. This case highlights the diagnostic and management complexities of biopsy-negative giant cell arteritis in patients with severe atherosclerotic vascular disease, emphasizing the importance of clinical judgment and established classification criteria when imaging and biopsy results are inconclusive.