This paper summarizes a multi-year effort comparing the new-generation wide-base tires (NG-WBT) and dual-tire assembly from a holistic point of view. The tires were compared considering not only pavement damage but also environmental impact. Numerical modeling, prediction methods, experimental measurements, and life-cycle assessment were combined to provide recommendations about the use of NG-WBT. A finite element (FE) approach considering variables that are usually omitted in the conventional analysis of flexible pavement was used for modeling pavement structures combining layer thickness, material properties, tire load, tire-inflation pressure, and pavement type (interstate and low volume). A prediction tool, ICT-Wide, was developed based on an artificial neural network to obtain critical pavement responses in cases excluded from the FE analysis matrix. Based on the bottom-up fatigue cracking, permanent deformation, and international roughness index, the life-cycle energy consumption, cost, and green-house gas emissions were estimated. To make this research useful for state departments of transportation and practitioners, a modification to AASHTOware is proposed to account for NG-WBT. The revision is based on two adjustment factors, one accounting for the discrepancy between the AASHTOware approach and the FE model of this study, and the other addressing the impact of NG-WBT. Although greater pavement damage may result from NG-WBT, for the analyzed cases, the extra pavement damage may be outweighed by the environmental benefits when NG-WBT market penetration is considered.