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Background: Intracranial fusiform aneurysms represent a rare but clinically aggressive subtype of cerebrovascular disease, characterized by circumferential arterial dilation and a high risk of growth, ischemic complications, and rupture. Unlike saccular aneurysms, fusiform lesions lack well-established medical therapies to prevent progression or stabilize the aneurysm wall. Tumor necrosis factor-alpha (TNF-α) has emerged as a central mediator of aneurysm-associated inflammation and vascular remodeling, raising interest in TNF-α modulation as a potential therapeutic strategy. This study aimed to systematically review and synthesize the available clinical and translational evidence evaluating TNF-α signaling and anti-TNF-α therapies in the context of intracranial fusiform aneurysms. Methods: A systematic literature search was conducted in PubMed/MEDLINE, Embase, and Google Scholar from database inception through February 2026 in accordance with PRISMA guidelines. Eligible studies included human, animal, and translational investigations examining TNF-α biology or anti-TNF-α interventions in relation to intracranial fusiform aneurysms, intracranial dolichoectasia, or vertebrobasilar dolichoectatic aneurysms. Study selection, deduplication, and screening were performed using Covidence systematic review software. Extracted outcomes included aneurysm growth, rupture, ischemic events, imaging characteristics, inflammatory signaling, and vascular remodeling. Given substantial heterogeneity in study design and outcome reporting, findings were synthesized narratively using structured evidence mapping. Results: From the 368 records identified, 14 studies met inclusion criteria following full-text review. Included studies encompassed preclinical models, translational mechanistic investigations, and limited clinical observational data. Across experimental models, TNF-α signaling was consistently associated with macrophage infiltration, matrix metalloproteinase activation, vascular smooth muscle cell phenotypic modulation, and aneurysm wall degeneration. TNF-α inhibition was associated with reduced aneurysm progression and rupture in preclinical settings, including when initiated after aneurysm formation. Clinical evidence remains limited but suggests a potential association between TNF-α modulation and aneurysm stability, although direct therapeutic data in intracranial fusiform aneurysm populations are sparse. Conclusions: The existing translational and preclinical evidence supports a contributory role for TNF-α-mediated inflammation in the progression of intracranial fusiform aneurysms and suggests that TNF-α inhibition may represent a promising disease-modifying strategy. However, clinical data remain insufficient to support routine therapeutic use. Prospective observational studies and early-phase clinical trials are needed to define the safety, timing, and efficacy of anti-TNF-α therapies in patients with intracranial fusiform aneurysms.