AbstractDuring storage, duloxetine hydrochloride may have an unexpected cross reaction with enteric coated acrylic resin, which may affect the product quality. Solve the problem of cross-reaction between the Duloxetine enteric-coated tablets core and coated enteric materials and improve the quality of the products. Duloxetine enteric-coated tablets’ core formulation and isolation layer prescription were designed and compared with duloxetine enteric-coated tablets sold on the market. Then, we measured the dissolution rate, content, and releasing rate of prepared duloxetine enteric-coated tablets. In the formulation of tablets core, prescription 3 had advantages in particle mobility, disintegration time, and dissolution rate. Prescription 5 was stable during the coating process, and the dissolution residue in the cup was relatively good, showing obvious dissolution advantages. Thus, prescription 5 was selected as the isolation layer prescription. The most suitable adhesive for the preparation of Duloxetine hydrochloride enteric-coated tablets was povione K30 dissolved in ethanol solution with 1/2 of the prescription amount. When 1.3 g colloidal silica was added to the prescription and the dosage of magnesium stearate was 1.48 g, the dissolution rate of the drug could be relatively improved. The ratio of sucrose and talc was 138/8.7, which could effectively configure the coating solution with a solid content of 15–20% to make the coating smooth.