BACKGROUND: Extreme cold and heat have been linked to an increased risk of occupational injuries. However, the evidence is still limited to a small number of studies of people with relatively few injuries and with a limited geographic extent, and the corresponding economic effect has not been studied in detail. OBJECTIVES: We assessed the relationship between ambient temperatures and occupational injuries in Spain along with its economic effect. METHODS: the daily number of occupational injuries that caused at least one day of leave and the daily maximum temperature were obtained for each Spanish province for the years 1994-2013. We estimated temperature-injuries associations with distributed lag nonlinear models, and then pooled the results using a multivariate meta-regression model. We calculated the number of injuries attributable to cold and heat, the corresponding workdays lost, and the resulting economic effect. RESULTS: The study included 15,992,310 occupational injuries. Overall, 2.72% [95% confidence interval (CI): 2.44-2.97] of all occupational injuries were attributed to nonoptimal ambient temperatures, with moderate heat accounting for the highest fraction. This finding corresponds to an estimated 0.67 million (95% CI: 0.60-0.73) person-days of work lost every year in Spain due to temperature, or an annual average of 42 d per 1,000 workers. The estimated annual economic burden is €370 million, or 0.03% of Spain's GDP (€2,015). CONCLUSIONS: Our findings suggest that extreme ambient temperatures increased the risk of occupational injuries, with substantial estimated health and economic costs. These results call for public health interventions to protect workers in the context of climate change. https://doi.org/10.1289/EHP2590.