This study evaluated the effects of dietary nucleotide supplementation in Pacific white shrimp, Litopenaeus vannamei, cultured in Indonesia. A total of 22,500 shrimp receiving diets in which fish meal (FM) had been partially replaced with vegetable protein sources were classified into five study groups (4500 shrimp/group) and received different diets for 110 days: 10FM (control group; 10% FM), 6FM (6% FM—low FM and no nucleotide supplementation), 10FMN (10% FM; 0.1% nucleotides), 8FMN (8% FM; 0.1% nucleotides) and 6FMN (6% FM; 0.1% nucleotides). Growth performance, body composition, total hemocyte count (THC), lysozyme activity, and hepatopancreas histopathology were assessed. Organoleptic evaluation and profitability assessments were also performed. In addition, shrimp resistance to a Vibrio harveyi challenge was studied in shrimps after having received the diets for 30 days. Results showed that reducing FM had a negative impact on growth performance and hepatopancreas morphology. Adding nucleotides resulted in better performance and profitability, a healthier histomorphological appearance of the hepatopancreas, and significantly higher survival rates upon challenge with V. harveyi, while it did not negatively affect organoleptic parameters. In conclusion, nucleotide supplementation could be useful for optimizing performance, profitability, and disease resistance in shrimp cultured under intensive outdoor pond conditions.