Introduction Until now, estimates of the Global Burden of Disease (GBD) have mainly been produced on national or regional levels. These general estimates, however, are less useful for city governments who have to take decisions on local scales. To address this gap, we focused on the city-level burden of disease (BD) due to exposures affected by urban and transport planning. We conducted a BD assessment using the Urban and Transport Planning Health Impact Assessment (UTOPHIA) tool to estimate annual preventable morbidity and disability-adjusted life-years (DALYs) under compliance with international exposure recommendations for physical activity (PA), exposure to air pollution, noise, heat, and access to green spaces in Barcelona, Spain. Methods Exposure estimates and morbidity data were available for 1,357,361 Barcelona residents ≥ 20 years (2012). We compared recommended with current exposure levels to estimate the associated BD. We quantified associations between exposures and morbidities and calculated population attributable fractions to estimate the number of attributable cases. We calculated DALYs using GBD Study 2015 background DALY estimates for Spain, which were scaled to Barcelona considering differences in population size, age and sex structures. We also estimated annual health costs that could be avoided under compliance with exposure recommendations. Results Not complying with recommended levels for PA, air pollution, noise, heat and access to green spaces was estimated to generate a large morbidity burden and resulted in 52,001 DALYs (95% CI: 42,866–61,136) in Barcelona each year (13% of all annual DALYs). From this BD 36% (i.e. 18,951 DALYs) was due to traffic noise with sleep disturbance and annoyance contributing largely (i.e. 10,548 DALYs). Non-compliance was estimated to result in direct health costs of 20.10 million € (95% CI: 15.36–24.83) annually. Conclusions Non-compliance of international exposure recommendations was estimated to result in a considerable BD and in substantial economic expenditure each year in Barcelona. Our findings suggest that (1) the reduction of motor traffic together with the promotion of active transport and (2) the provision of green infrastructure would result in a considerable BD avoided and substantial savings to the public health care system, as these measures can provide mitigation of noise, air pollution and heat as well as opportunities for PA promotion.