Diisocyanates are a group of chemicals used in many different applications, such as plastics, foams, coatings, adhesives, and sealants. Prolonged occupational exposure can result in severe asthma. This case report presents a non-smoking male without any previous respiratory disease, where severe obstructive airway symptoms developed during a single event with high airborne exposure to polyurethane foam containing methylene diphenyl diisocyanate during the coating of a large vehicle. The subject was subsequently diagnosed with occupational asthma based on a significant variability in a two-week peak expiratory flow curve and a positive metacholine challenge. Despite aborted exposure and optimized asthma treatment, the subject continued to experience debilitating airway symptoms. This case report demonstrates that severe asthma can develop following a single exposure to polyurethane foam containing methylene diphenyl diisocyanate, underscoring the importance of preventive measures in workplaces where such chemicals are used.