A 6 wk trial was conducted to evaluate the effects of nucleotide supplementation in improving performance, nutrient digestibility, and immune blood profiles so as to reduce foot-and-mouth disease (FMD) vaccine stress in growing pigs. A total of 120 growing pigs [(Yorkshire × Landrace) × Duroc] with an average body weight (BW) of 25.76 ± 1.83 kg were used. Pigs were allocated to one of three treatments (eight pens per treatment; three barrows and two gilts per pen) based on BW and sex. Pigs were injected with FMD vaccine at 84 d of age (2 wk after experiment started). Dietary treatments consisted of (1) CON: corn–soybean-meal-based diet, (2) NUC1: CON + 0.5% nucleotide, and (3) NUC2: CON + 1.0% nucleotide. In the current study, the growth performance of gain:feed ratio (G:F), the apparent total tract digestibility of dry matter and nitrogen was linearly (P < 0.05) increased with the increasing level of nucleotide. After injection, the concentration of cortisol and epinephrine was decreased (P < 0.05) linearly in nucleotide treatments. In conclusion, nucleotide supplementation to FMD vaccinated pigs showed positive effects on improving performance, immune system health, and reducing vaccine stress in growing pigs.