Abstract Background Past research has shown that individuals who have had experiences of out-of-home care (OHC) in childhood have increased risks of premature mortality. Prior studies also suggest that these individuals are more likely to follow long-term trajectories that are characterised by economic, work-, and health-related disadvantages, compared to majority population peers. Yet, we do not know the extent to which such trajectories may explain their elevated mortality risks. The aim of this study is therefore to examine whether trajectories of economic, work-, and health-related disadvantages in midlife mediate the association between OHC experience in childhood and subsequent all-cause mortality. Methods Utilising longitudinal Swedish data from a 1953 cohort (n = 14,294), followed from birth up until 2008 (age 55), this study applies gender-specific logistic regression analysis to analyse the association between OHC experience in childhood (ages 0–19; 1953–1972) and all-cause mortality (ages 47–55; 2000–2008). A decomposition method developed for non-linear regression models is used to estimate mediation by trajectories of economic, work-, and health-related disadvantages (ages 39–46; 1992–1999), as indicated by social welfare receipt, unemployment, and mental health problems. To account for selection processes underlying placement in OHC, an alternative comparison group of children who were investigated by the child welfare committee but not placed, is included. Results The results confirm that individuals with experience of OHC have more than a two-fold increased risk of all-cause mortality, for men (OR: 2.10, 95% CI: 1.42–3.11) and women (OR: 2.23, 95% CI: 1.39–3.59) alike. Approximately one-third (31.1%) of the association among men, and one-fourth (27.4%) of the association among women, is mediated by the long-term trajectories of economic, work-, and health-related disadvantages. The group who were investigated but not placed shows similar, yet overall weaker, associations. Conclusions Individuals who come to the attention of the child welfare services, regardless of whether they are placed in out-of-home care or not, continue to be at risk of adverse outcomes across the life course. Preventing them from following trajectories of economic, work-, and health-related disadvantages could potentially reduce their risk of premature death.