Dome structures have been used extensively for industrial, residential, and military infrastructure. Therefore, it is necessary to understand the damage risk potential for such structures for blast-resistant design considerations. This paper investigates the effect of blast load variability on the design value and the structural dynamic response. Therefore, the sources of uncertainty in the external blast load on dome structures were discussed firstly. Then based on the probabilistic blast load model for the dome, the rationality of a deterministic mass-increase safety method was assessed. It was found that previous deterministic design method cannot provide a consistent and sound assurance factor or reliability index on the entire dome roof. In addition, it was also proved that the assurance-based load method fails to ensure compliance with structural safety design standards on the dome roof when compared with the reliability-based blast method. A sensitivity analysis on the probabilistic blast load was conducted, and the results indicate that stand-off distance and explosive mass both act as dominant sources to influence the mean and variability of blast load. Therefore, based on the Latin hypercube sampling method, a reliability-based external blast load factor technique was proposed. This technique was further used to estimate structural damage levels of a single-layer reticulated dome under different reliability requirements, associated with a low, medium, and high level of protection grades for a specific explosion scenario, and it indicated that this technique can be useful in the building design to achieve a higher structural anti-explosion capacity. This study herein can serve as a reference for the calculation method of designed blast load.