Research on evaluating highway bridge performance through vehicle-bridge interaction (VBI) analysis has made significant advancements. However, when assessing driving comfort, using vehicle acceleration instead of human acceleration poses challenges in accurately representing comfort. First, the paper proposes a finite element analysis method for human-vehicle-bridge spatial interactions (HVBSIs). Then, the importance of wheel path roughness difference is explored when assessing driving comfort. Furthermore, a new method for evaluating driving comfort that includes human and vehicle vibration responses has been proposed, and a simulation example of the steel-concrete composite beam bridge (SCCBB) is used to verify the effectiveness of the proposed method. The results demonstrate that the HVBSI analysis method effectively simulates the interconnected vibrations of the human body, the spatial vehicle model, and the three-dimensional (3D) bridge model. Differences in wheel path roughness significantly impact the roll vehicle vibration responses, which are crucial in driving comfort analysis. The driver’s body vibration response is essential for evaluating driving comfort, and its inclusion leads to increased comfort indices values. In comparison to traditional methods, the overall vibration total value (OVTV) increases by a maximum of 109.04%, and the level of weighted vibration (Leq) increases by a maximum of 6.74%. This leads to an upgrade from grade IV to grade V in terms of comfort level, indicating a reduced comfort.