Many researchers have carried out experimental and numerical investigations to examine building structures’ response to explosive loads. Studies of bridges subjected to blast loads are limited. Hence, in this study, we present a case study on a cable-stayed bridge, namely, Charles River Cable-Stayed Bridge-Boston, to assess its robustness and resistance against the progressive collapse resulting from localized failure due to blast loads. Three different blast scenarios are considered to interpret the bridge performance to blast loads. To monitor the progressive failure mechanisms of the structural elements due to blast, pre-defined plastic hinges are assigned to the bridge deck. The results conclude that the bridge is too weak to sustain the blast loads near the tower location, and the progressive collapse is inevitable. Hence, to preserve this cable-stayed bridge from local and global failure, structural components should be more reinforced near the tower location. This case study helps the designer better understand the need for blast resistance design of cable-stayed bridges.