Objective: To observe the therapeutic effect of motivational interview intervention combined with paroxetine tablets on postpartum depression patients and its influence on the levels of general self-efficacy scale (GSES), CD-RISC score, progesterone and estradiol. Methods: 80 patients with postpartum depression were selected as the research object. According to the random number table method, they were divided into control group (40 cases) and observation group (40 cases). Both groups of patients were given paroxetine tablets, and the observation group was given motivational interview intervention on this basis. The differences of GSES, CD-RISC score, maternal role adaptability, progesterone and estradiol levels between the two groups before and after intervention were observed Results: There was no significant difference in CD-RISC and GSES scores between the two groups before intervention (all P > 0.05). After the intervention, the CD-RISC and GSES scores of the patients in the observation group were higher than those in the control group, and the differences were statistically significant (all P < 0.05). There was no significant difference in mother′s role adaptability scores between the two groups before intervention (P > 0.05). After the intervention, the scores of mother′s role happiness, the influence of newborn on maternal life, the ability to take care of newborn′s daily life and belief in the observation group were higher than those in the control group, and the differences were statistically significant (all P < 0.05). There was no significant difference in anxiety and depression scores between the two groups before intervention (P > 0.05). After the intervention, the scores of self-rating anxiety scale (SAS) and self-rating depression scale (SDS) in the observation group were lower than those in the control group, and the differences were statistically significant (all P < 0.05). There was no significant difference in progesterone and estradiol levels between the two groups before intervention (all P > 0.05). After intervention, the levels of progesterone and estradiol in the observation group were higher than those in the control group (all P < 0.05). Conclusion: Motivation interview intervention combined with paroxetine tablets has a good therapeutic effect on patients with postpartum depression, which can improve the depression, progesterone and estradiol levels of patients, and improve the self-efficacy of patients.