ackground: A major industrial fire accident occurred in a tire manufacturing factory in Daejeon, Korea, on 12 March 2023 and lasted for 3 d, generating air pollutant emissions. Although evidence regarding the health effects of urban fires is limited, residents near tire factory may have experienced health hazards due to smoke exposure from fire plumes. Objectives: Capitalizing on the timing of this fire incident as a natural experiment, we estimated the attributable excess air pollution exposure and associated disease development among residents living near the tire factory. Methods: We used the generalized synthetic control method to estimate air pollution exposure and health burden attributable to the accident among residents living in smoke-exposed districts. Based on satellite images and air pollution monitoring results, three administrative districts (within 1.2km from the factory) were defined as smoke-exposed, and the other 79 districts of Daejeon were defined as controls. Among the 11 monitoring stations in Daejeon, the station located 500m from the factory was used to estimate excess air pollution exposure (PM10, PM2.5, NO2, O3, SO2 , and CO) for residents in the exposed districts. The number of daily district-level disease-specific incidence cases were acquired from the National Health Insurance Database and used to estimate excess health burden resulting from the fire. Results: During the first week following the factory fire, residents of exposed districts had an estimated excess exposure to 125.2 [95% confidence interval (CI): 44.9, 156.7] μg/m3 of PM10, 50.4 (95% CI: 12.7, 99.8) ppb of NO2, and 32.0 (95% CI: 21.0, 35.9) ppb of SO2. We also found an average increase in the incidence cases of other diseases of upper respiratory tract [20.6 persons (95% CI: 6.2, 37.4)], lung disease due to external agents [2.5 persons (95% CI: 2.1, 3.3)], urticaria and erythema [5.9 persons (95% CI: −0.6 , 11.2)], and episodic and paroxysmal disorders [8.5 persons (95% CI: 3.7, 13.4)] in exposed districts. Discussion: Excessive air pollution exposure and disease incidence were identified among residents living close to the tire factory. Preventive measures, such as a warning system, to avoid health impacts to people breathing fire-related pollution may be beneficial for communities impacted by such events. https://doi.org/10.1289/EHP14115.