Ultra-High Performance Concrete (UHPC) is a modern class of cementitious composite materials. With superior mechanical properties (compressive strength over 130 MPa and tensile strength over 6 MPa) and durability, it has gained increasing structural applications worldwide. The current design of prestressed UHPC girders commonly fails due to the fracture of prestressing strands quickly after the crack localization of UHPC, rather than after the crushing of the cementitious matrix as expected in traditional concrete girders. When failing quickly after crack localization, girders exhibit low structural ductility and inadequate safety warnings before failure (i.e., nearly invisible cracking and compressive damage). To address these challenges, this study develops a novel design method for the prestressed UHPC girders. Four-point bending tests are conducted on two full-scale girders: one girder represents the current practice in China and the state-of-the-art design in the US, while the other represents the proposed new design. Test results demonstrate that the new design maintains the load capacity after crack localization and exhibits a ductile failure after the formation of multiple localized cracks and significant UHPC crushing, which provides many failure warnings. Compared to the currently common design, the new design increases the deflection capacity by 109% and peak load by 27%, while reducing the total initial cost by 4% and the ratio of total costs to peak load by 25%, bringing significant advantages for structural ductility, safety, and cost-effectiveness. Finally, a failure mode prediction method is developed and validated for prestressed UHPC girders.