National longitudinal studies that investigate the long-term association between early family life and mental health in middle and older adulthood are limited. This study aims to fill the gap by examining the protective effect of positive childhood relationships with mothers and fathers and parental support against depression among women and men in middle and late adulthood. The sample of 12,606 adults (7319 females; 5287 males) from the US Health and Retirement Study was nationally representative with the inclusion of 7 depression measures from 2008 to 2018. Two depression measures, CESD-8 scale and binary indicators of severe depressive symptoms, were used. Generalized estimation equations (GEE)-negative binomial models were estimated for CESD-8 and GEE-logit models were estimated for the binary indicator of severe depression. This study aimed to assess how positive parent-child relationships and maternal support protect the mental health of women and men in adulthood. Other risk and psychosocial factors, such as childhood depression, traumatic life events, stressful life events, marital status, and social support in adulthood were adjusted for. Positive childhood relationships with mothers, fathers, or both parents and increased maternal support were associated with a lower risk of depression among both females and males from middle to old age, even if they experienced trauma, stressful life events, divorce, singlehood, widowhood, or little social support. Females benefited more psychologically than males from positive mother-daughter relationships and high-quality relationships with both parents. However, compared to mother-child relationships, positive father-child relationships protected men better psychosocially than females. Findings underscore the importance of fathers' roles in promoting their children's, especially sons', emotional well-being. Interventions in early mother-child and father-child relationships and parental support are crucial for healthy aging in mental development.