Synthetic vascular grafts, such as expanded polytetrafluoroethylene (ePTFE), are commonly used for large vessel surgeries [internal diameter (ID) ≥ 10 mm] but present significant challenges in medium to small vessels (ID < 10 mm) due to increased risks of thrombosis, stenosis, and infection. In this study, we developed a small-diameter vascular graft using decellularized human amniotic membrane (DAM graft) (ID = 6 mm) and transplanted it into porcine carotid arteries, comparing it with ePTFE grafts to assess inflammation, biocompatibility, patency, and overall function. One-week post-implantation, ultrasound imaging confirmed blood patency in both graft types. However, after one-month, gross examination revealed pronounced neointimal hyperplasia in ePTFE grafts, while DAM grafts maintained open lumens without signs of stenosis or thrombosis. Histological analysis showed extensive fibrous tissue formation in ePTFE grafts, resulting in luminal narrowing, whereas DAM grafts displayed sustained lumen patency and vascular integration. Immunofluorescence confirmed reduced inflammation and improved tissue organization in DAM grafts, characterized by lower macrophage infiltration and better cellular architecture. These findings suggest that DAM grafts offer superior biocompatibility and significantly lower risks of neointimal hyperplasia, making them a promising alternative for small-diameter vascular surgeries compared to ePTFE grafts.