In recent decades, some of the main goals of pavement engineers have been to increase bearing capacity, enhance tensile strength, and improve the moisture susceptibility of asphalt mixtures. Because moisture and frost intensify the damage caused by traffic loads on pavements in cold climates, the life and safety of asphalt pavements in this climate are reduced. Finally, cracking at low temperatures and moisture damage leads to a decrease in the serviceability of asphalt pavement in cold climates relative to temperate climates. Hence, a comprehensive and accurate program is necessary to estimate the fracture toughness and moisture susceptibility of asphalt mixtures in cold climates. In recent years, nanotechnology has become very popular due to its unique features in enhancing the operation of bitumen and asphalt mixtures. For this purpose, in this study, the impact of nano-TiO2 on pavement performance against cracking and moisture susceptibility is investigated. To achieve this objective, SCB specimens were fabricated with different ratios of nano-TiO2 (0.0% and 0.9%) and studied at the three temperatures of −5°C, −15°C, and −25°C under pure mode I, pure mode II, and four distinct mixed-mode (I/II) loading (Me=0.2, Me=0.4, Me=0.6, Me=0.8) for various crack geometry, including vertical and angular cracks for which the crack angle is 45° in samples with angular cracks. In addition, the indirect tensile strength (ITS) test was employed to estimate the moisture susceptibility. The results indicated that modifying the asphalt mixture properties with 0.9% nano-TiO2 had a significant impact on the fracture behavior of the samples in both vertical and angular cracks under all temperatures. Additionally, with the application of nano-TiO2 and decreasing temperature, the fracture toughness of the samples increased. Furthermore, the findings displayed that the employment of 0.9% nano-TiO2 reduced the moisture susceptibility of asphalt mixtures by approximately 6%.