Vehicle-bridge interaction is the core for a variety of applications, including vehicle vibration, bridge vibration, bridge structural health monitoring, weight-in-motion, bridge condition inspection, and load rating. These applications give rise to a great interest in pursuing a high-efficiency method that can tackle intensive computation in the context of vehicle-bridge interaction. This paper studies the accuracy and efficiency of discretizing the beam in space as lumped masses using the flexibility method and as finite elements using the stiffness method. Computational complexity analysis is carried out along with a numerical case study to compare the accuracy and efficiency of both methods against the analytical solutions. It is found that both methods result in a similar level of accuracy, but the flexibility method overperforms the stiffness method in terms of computational efficiency. This high efficiency algorithm and corresponding discretization schema are applied to study the dynamics of vehicle-bridge interaction. A system of coupled equations is solved directly for a simply supported single-span bridge and a four-degree-of-freedom vehicle modeling. Pavement roughness significantly influences dynamic load coefficient, suggesting preventative maintenance or timely maintenance of pavement surface on a bridge, to reduce pavement roughness, is of significant importance for bridge’s longevity and life-cycle cost benefit. For class A and B level pavement roughness, the dynamic load coefficient is simulated within 2.0, compatible with specifications of AASHTO standard, Australian standard, and Switzerland standard. However, the Chinese code underestimates the dynamic load coefficient for a bridge with a fundamental frequency of around 4 Hz. The proposed method is applicable to different types of bridges as well as train-bridge interaction.