Background Social support and maternal self-efficacy are important protective factors against depression. However, the contribution of these variables to postpartum depression in the context of persistent maternal fatigue and prolonged unrestrained infant crying is unclear. Objectives This study aimed to explore possible mediating roles of maternal chronic fatigue, infant crying intensity, and frustration as a maternal emotional response to infant crying on the relationship between social support, maternal self-efficacy and maternal depression. Methods The study employed cross-sectional data from 524 infant mothers. 73.1 % were mothers of their first child. A statistical analysis employed structural equation modeling (SEM) to estimate direct, indirect, and total effects in the relationships between the study variables. Results The hypothetical model demonstrated a good fit to the data and explained the depressive symptoms in mothers (R2 = 54 %). The role of chronic maternal fatigue as a significant potential mediator in the severity of depressive symptoms in mothers of infants was confirmed. Chronic fatigue is exacerbated directly by low self-efficacy and low support from the partner, family members, and infant crying. Furthermore, it is indirectly intensified by mother's frustration as an emotional response to infant crying. Conclusion Chronic fatigue in mothers of crying infants plays an important mediating role in the relationship between social support, self-efficacy, and depressive symptoms. Partners and relatives of mothers with chronic fatigue should be aware that chronic fatigue increases the risk of depression. These findings may be essential in promoting maternal health and well-being during the transition to parenthood.