Background: Car-dependent city planning has resulted in high levels of environmental pollution, sedentary lifestyles and increased vulnerability to the effects of climate change. The Barcelona Superblock model is an innovative urban and transport planning strategy that aims to reclaim public space for people, reduce motorized transport, promote sustainable mobility and active lifestyles, provide urban greening and mitigate effects of climate change. We estimated the health impacts of implementing this urban model across Barcelona. Methods: We carried out a quantitative health impact assessment (HIA) study for Barcelona residents >= 20 years (N= 1,301,827) on the projected Superblock area level (N= 503), following the comparative risk assessment methodology. We 1) estimated expected changes in (a) transport-related physical activity (PA), (b) air pollution (NO2), (c) road traffic noise, (d) green space, and (e) reduction of the urban heat island (UHI) effect through heat reductions; 2) scaled available risk estimates; and 3) calculated attributable health impact fractions. Estimated endpoints were preventable premature mortality, changes in life expectancy and economic impacts. Results: We estimated that 667 premature deaths (95% CI: 235-1,098) could be prevented annually through implementing the 503 Superblocks. The greatest number of preventable deaths could be attributed to reductions in NO2 (291, 95% PI: 0-838), followed by noise (163, 95% CI: 83-246), heat (117, 95% CI: 101-137), and green space development (60, 95% CI: 0-119). Increased PA for an estimated 65,000 persons shifting car/motorcycle trips to public and active transport resulted in 36 preventable deaths (95% CI: 26-50). The Superblocks were estimated to result in an average increase in life expectancy for the Barcelona adult population of almost 200 days (95% CI: 99-297), and result in an annual economic impact of 1.7 billion EUR (95% CI: 0.6-2.8). Discussion: The Barcelona Superblocks were estimated to help reduce harmful environmental exposures (i.e. air pollution, noise, and heat) while simultaneously increase PA levels and access to green space, and thereby provide substantial health benefits. For an equitable distribution of health benefits, the Superblocks should be implemented consistently across the entire city. Similar health benefits are expected for other cities that face similar challenges of environmental pollution, climate change vulnerability and low PA levels, by adopting the Barcelona Superblock model.