It is estimated that over 100 million people worldwide are affected by the substance use of a close relative and often experience related adverse health and social outcomes. There is a growing body of literature evaluating psychosocial interventions intended to reduce these adverse outcomes. We searched the international literature, using rigorous systematic methods to search and review the evidence for effective interventions to improve the wellbeing of family members affected by the substance use of an adult relative. We synthesised the evidence narratively by intervention type, in line with the systematic search and review approach. Sixty-five papers (from 58 unique trials) meeting our inclusion criteria were identified. Behavioural interventions delivered conjointly with the substance user and the affected family members were found to be effective in improving the social wellbeing of family members (reducing intimate partner violence, enhancing relationship satisfaction and stability and family functioning). Affected adult family members may derive psychological benefit from an adjacent individually focused therapeutic intervention component. No interventions fully addressed the complex multidimensional adversities experienced by many families affected by substance use. Further research is needed to determine the effect of a multi-component psychosocial intervention, which seeks to support both the substance user and the affected family member.