Cerebral aneurysms (CA) are a serious condition characterized by the bulging of a blood vessel in the brain, which can lead to rupture and life-threatening bleeding. The pathophysiology of CA involves complex processes, particularly inflammation and macrophage infiltration. Phoenixin-14 (PNX-14) is a neuropeptide with diverse biological effects, including roles in reproduction, energy homeostasis, and inflammation. Recent evidence has highlighted the therapeutic potential of PNX-14 in various conditions. Notably, PNX-14 has demonstrated neuroprotective effects in the central nervous system, and we hypothesized that it could also offer vascular protection in the context of CA. In this study, we demonstrate that serum PNX-14 levels are reduced in patients and rat models with CA compared to healthy controls. Our findings show that PNX-14 administration significantly reduces aneurysmal size in a rat model with left renal artery ligation. Furthermore, PNX-14 mitigates the inflammatory response by inhibiting the expression of IL-1β and MCP-1 at both the mRNA and protein levels in the Circle of Willis (COW) region. PNX-14 treatment also decreases the levels of MMP-2 and MMP-9 in the COW region. Mechanistically, PNX-14 suppresses macrophage infiltration and inhibits the activation of the p38/NF-κB signaling pathway. These findings suggest that PNX-14 could be a promising therapeutic agent for the prevention and treatment of CA.