In recent years, the accidents of out-of-control vehicles falling off bridges appeared frequently, which caused huge losses to people's lives and properties. To improve the protection performance of bridge anti-collision guardrail, some feasible methods should be taken into consideration, so that the risk of such accidents can be reduced. Therefore, a novel bridge road-car isolation guardrail was proposed, and the inverted U-shaped section was adopted, and the anchorage was connected to the concrete curb as a whole. The mechanical properties of the guardrail were discussed by applying a refined finite element model. The results show that the two guardrails satisfy the requirements under the standard impact load effects, and the maximum deformation of the novel guardrail is approximately half of the traditional one. When the deformation reaches the maximum value, the ultimate bearing capacity of the new guardrail increases by 58% compared with the traditional one, and the bolt stress and deformation declined by 52% and 30% respectively. This proves that the new guardrail could not only give full play to the suppression effect of masonry weight on vehicle impact and the sheer performance of anchor bolts but also significantly increase the lateral stiffness of the guardrail with the inverted U-shaped section. Compared with the traditional guardrail, the collision resistance of the new was significantly improved. In addition, the prefabricated form can effectively reduce the construction and maintenance costs, providing new solutions for the design and construction of many bridge crash guardrails.