Objective To evaluate the therapeutic effect and safety of Bupropion hydrochloride sustained-release tablets in the treatment of depression. Methods A total of 48 patients meeting the diagnostic criteria of depression of CCMD-3 were randomly treated with Bupropion hydrochloride sustained-release tablets or Fluoxetine tablets for 42 days. Hamilton depression rating scale, Hamilton anxiety rating scale, clinical global impression and treatment emergent symptom scale were used to evaluate the therapeutic effect. Blood routine test, urine routine test and electrocardiogram were examined before and after the treatment. Results The effective rate of Bupropion hydrochloride sustained-release tablets [83% (20/ 24) ] was higher than that of Fluoxetine tablets [63% (15/ 24)], with a P value of 0.104. The incidence of adverse reactions was 46% (11/24) in both groups. Conclusion The therapeutic effect of Bupropion hydrochloride sustained-release tablets on depression is similar to that of Fluoxetine tablets, with mild adverse reactions to both treatments.