Road bridge designs are based on technical standards, which, to date, consider dynamic loading as equivalent static loads. Additionally, the few engineers who perform a dynamic analysis typically do not consider the effects of bridge-vehicle interaction and also simplify the road’s irregularity profile. Moreover, often, even when a simplified dynamic analysis is carried out and shows that there will be a high dynamic amplification factor (DAF), designers prefer to solve this problem by adopting high safety factors and thereby oversizing the bridge, rather than using energy dissipation devices that would allow reducing the amplitude of vibration. In this context, the present work proposes a complete methodology to minimize the dynamic response of road bridges by optimizing multiple tuned mass dampers (MTMD), taking into account the bridge-vehicle interaction, the random profile of pavement irregularities, and the uncertainties present in the coupled system and in the excitation. For illustrative purposes, the coupled vibration problem of a regular truck traveling on a random road profile over a typical Brazilian bridge is analyzed. Three different scenarios for the MTMD are considered. The proposed optimization problem is solved by employing the Whale Optimization Algorithm (WOA). The results showed the excellent ability of the proposed methodology, reducing the bridge’s DAF to acceptable values for all analyzed cases, considering or not the uncertainties present in the system. Furthermore, the results obtained by the proposed methodology are compared with results obtained using classical tuned mass damper (TMD) design methods, showing the best performance of the proposed optimization method. Thus, the proposed method can be employed to optimize MTMD, improving bridge design.