Superblocks can help to transform urban areas into pedestrian-centric neighborhoods. First launched in Barcelona, Spain, they are expected to reduce harmful environmental exposures, increase green space access and thereby provide substantial health benefits. However, few studies have examined the practicality and likely benefits of implementing Superblocks in other metropolitan areas. We developed a methodological framework to build a generalizable City of Los Angeles (LA) Superblocks Model and evaluate the predicted health benefits that would follow such an intervention. We derived and used five rules to guide the choice of arterial streets and candidate blocks and the choice of major bounding streets that could facilitate mobility across the metropolitan area. We next used the BenMap-CE model to perform a quantitative assessment of the health and economic benefits that would accompany five scenarios that would transform 5–50% of the residential areas in the City of LA to Superblocks. We found that the creation of superblocks resulted in significant reductions in hospital admissions and significant economic savings. The benefits were strongest when 5–10% of residential areas were transformed, but rapidly decreased as the threshold reached 30%. These results will help stakeholders determine the optimal balance between reduced car traffic and improved health outcomes. Moreover, we illustrated how to develop a Superblocks model for a highly versatile and populated metropolitan area like the City of LA and how the model can be used to assess the potential health benefits and benchmark the relationship between the scale of the Superblock implementation and the accompanying health benefits moving forward.