Objective To explore the mediating role of self-esteem on the relationship between prenatal depression and fatigue in pregnant women, so as to provide a reference for developing targeted intervention.Methods A total of 401 pregnant women from an outpatient department for antenatal examination were surveyed by using a general information questionnaire，the Edinburgh Postpartum Depression Scale (EPDS), the Self-Esteem Scale (SES), and the Fatigue Self-Assessment Scale (FSAS).Results The participants′ scores of the EPDS, SES and FSAS were 10.00(7.00,13.00), （32.28±4.00） and 8.93（3.57,25.00） respectively.Fatigue during pregnancy was positively correlated with prenatal depression and negatively correlated with self-esteem, while prenatal depression was negatively correlated with self-esteem (all P＜0.05).The mediating effect value of self-esteem on the relationship between prenatal depression and fatigue was 0.076, which accounted for 18.67% of the total effect.Conclusion The incidence of mild and moderate fatigue in pregnant women is high, and self-esteem plays a mediating role between prenatal depression and fatigue.It is suggested to improve pregnant women′s self-esteem and alleviate prenatal depression, thereby relieve their fatigue.