This research focused on predicting the performance of modified asphalt mixtures with high contents of nano-silica fume (NSF) using AASHTOWare Pavement ME Design software, which is the production version of the Mechanistic-Empirical Pavement Design Guide (MEPDG). The NSF was completely mixed with the virgin asphalt using a high-shear mixer at 160 °C and a speed of 2000 rpm for 1 hr. The physical- rheological properties of the control binder, as well as the binders modified with 30, 40, and 50% NSF by asphalt weight, were determined. The asphalt mixtures were prepared using control and NSF-modified binders by the conventional Marshall method. The predicted field pavement performance of both the control and NSF-modified asphalt mixtures in terms of rutting, longitudinal cracking, alligator fatigue cracking at three different climatic locations in Egypt (Aswan, Cairo, and Alexandria), and three design speeds (10, 55, and 95 kph) was evaluated. The simulations indicated that the NSF-modified mixtures outperformed the control mixture.