The invention discloses an esomeprazole sodium and sodium chloride injection and a preparation method thereof, and belongs to the technical field of an injection. Every 100 mL of the injection includes: 35-45 mg of esomeprazole sodium, 1.5-4.5 mg of edetate disodium, 6-10 mg of sodium hydroxide, 4-8 mg of sodium bicarbonate, 0.9 g of sodium chloride, and a proper amount of injection water. The invention further provides a preparation method of the injection. Through prescription optimization, sodium bicarbonate, sodium chloride and injection water are added in the prescription, wherein sodiumbicarbonate has an effect of buffering and adjusting the pH value and makes the pH value of the injection always maintain in an effective pH value range of a medicine. The injection can be directly used, so that pollution during a preparation process is prevented. The injection is good in stability and not prone to degrade. According to an accelerated test, the injection can be stored for 6 monthswith the efficacy only reduced by 5.5%. The injection can be stored for 12 months at the room temperature with the efficacy being 98% of the original efficacy, and meets the quality standard.