Nano-silica (NS) is an effective material to improve the strength and durability of high-performance concrete (HPC), but little information is available regarding its role in HPC response to long-term sulfate attack. In this study, six different dosages of NS (0%, 1%, 2%, 3%, 4%, and 5%) as cement partial replacement were mixed into HPC and the casted specimens were soaked in sulfate solution for different periods (0, 100, 200, and 300 days). The mass change, dynamic elastic modulus, compressive and splitting strength, microstructure morphology, and porosity characteristics of HPC specimens were measured by mass tests, mechanical properties tests, scanning electron microscopy (SEM), and nuclear magnetic resonance (NMR) tests. The results showed that the incorporation of NS decreased the mass loss, elevated the compressive and splitting strength, and reduced the porosity formation of HPC in front of sulfate attack. The percentage of 1% NS was among the most effective dosages as, after soaking for 300 days, it decreased the mass loss by 13.5%, elevated the elastic modulus as well as compressive and splitting strength by 50.4%, 31.7%, and 69.8% in comparison of unmodified HPC, respectively. The sulfate attack resistance was delayed in a higher (2–5%) mixed dosage, mainly due to the agglomeration of nano particles, especially after long-term reactions. This study can provide experimental references regarding the performance of HPC mixed with NS in front of sulfate attack.