"Diseases of despair," most prominently depressive and substance-related problems, diminish the prospects of many young adults, especially those with lower levels of education. Yet many young adults in that situation avoid these problems. Close relationships are thought to be a key factor underpinning risk and resilience among this group. To examine this premise, this study explored links, beyond potential confounders assessed in adolescence, between strengths and strains in the social domain and markers of despair in the early and mid-20s in a Canadian sample overrepresenting youth without postsecondary credentials (N = 543, 52% male, 23% non-White). Having a good general ability to maintain supportive relationships was associated with fewer depressive and substance-related symptoms. Furthermore, support and less strain in relationships with parents and friends were associated with fewer depressive symptoms in the early and mid-20s, while for romantic relationships, associations with depressive symptoms became more consistent and robust in the mid-20s. Therefore, support and strains in romantic relationships gradually gained prominence as a determinant of depressive symptoms as youth advanced in adulthood. For substance-related problems, significant associations emerged for strains in friendships only, in both the early and mid-20s. These results suggest that multiple aspects of relationships pose a risk for or protect from the development of diseases of despair in early adulthood and that their relative importance changes depending on outcomes and developmental timing. Thus, facilitating meaningful social connections and reducing the prevalence and impact of relationship strains might contribute to preventing diseases of despair among youth with lower educational attainment.