Objective: This study was conducted to analyze the relationship between the plasma concentration of duloxetine in patients with depression (MDD) and its therapeutic effect, compliance, and side effects. Methods: The participants in this study were 100 patients with MDD who visited our hospital between January 2019 and January 2020. They were divided into a low-dose group and a high-dose group and were treated with duloxetine 60 mg/d and 120 mg/d, respectively, for 6 weeks. Fasting venous blood was collected at 1, 3, and 6 weeks after treatment and concentration of duloxetine in the plasma was detected by high-performance liquid chromatography tandem mass spectrometry. Participants completed the Hamilton Inhibition Scale (HAMD) and Hamilton Anxiety Scale (HAMA) before treatment and 1, 3, and 6 weeks after treatment to analyze duloxetine's therapeutic effect. Tess scores were calculated before treatment and 1, 3, and 6 weeks after treatment to compare the drug's side effects between the two groups. The groups' compliance was analyzed before treatment and 1, 3, and 6 weeks after treatment. Pearson linear correlation was used to determine the correlation between plasma concentration and HAMD, HAMA, Tess scores. Results: The plasma concentrations of the high-dose group were significantly higher than those of the low-dose group at all points in time (P<.05). The HAMD scores of the high-dose group were significantly lower than those of the low-dose group at all points in time after treatment (P<.05). The HAMA scores of the high-dose group were significantly lower than those of the low-dose group at all points in time after treatment (P<.05). The Tess scores of the high-dose group were higher than those of the low-dose group at all points in time after treatment (P>.05). There was no significant difference in treatment compliance between the two groups at each point in time (P>.05). There was a significant negative correlation between plasma concentration and HAMD scores at 1, 3, and 6 weeks after treatment in the low-dose group (P < .05). There was a significant negative correlation between plasma concentration and HAMD scores at 1, 3, and 6 weeks after treatment in the high-dose group (P<.05). There was a significant negative correlation between plasma concentration and HAMA scores at 1, 3, and 6 weeks after treatment in the low-dose group (P<.05). There was a significant negative correlation between plasma concentration and HAMD scores at 1, 3, and 6 weeks after treatment in the high-dose group (P<.05). Conclusion: Duloxetine reduced symptoms of depression and anxiety in patients with MDD according to its dose. HAMA and HAMD scores were negatively correlated with duloxetine's plasma concentration. Side effects and patient compliance were not correlated with its plasma concentration.