Innovative construction materials have been recently developed to create sustainable infrastructure and buildings. For example, nano-TiO2 has been added to mortars and concrete to develop self-cleaning and air-purifying buildings and infrastructure. In particular, air-purifying and self-cleaning tunnels have been very attractive for reducing both air pollution levels and infrastructure maintenance activities. Although these are very promising results, implementation of these materials is still limited due to high costs, environmental and health concerns. Therefore, the sustainability assessment of a nano-TiO2 loaded mortar for the potential implementation in the Colombia Avenue Tunnel located in Santiago de Cali, Colombia, was conducted. This major urban infrastructure project, which is 670 m long, 5.5 m tall, and 14 m wide, is located near the city center in a high-traffic zone with a potential photocatalytic area of 15,410 and volumes of approximately 5,000 vehicles per hour. The sustainability assessment was performed across three critical domains: environment, human health, and economy. So, by determining the environmental, human health, and economic impacts using a life cycle assessment (ISO 14040 Standard), ReCiPe methodology (acronym from Radboud University, RIVM, CML, and PRé Consultants), and life cycle cost (ISO 15686), respectively, the results show significant environmental benefits that improve human health without any recognizable hazard. These benefits justify the necessary economic investment to transform the Colombia Avenue Tunnel into a self-cleaning and air-purifying transport infrastructure.