The United States is in the midst of an opioid epidemic, which is leading to approximately 130 deaths each day. While research on family-based approaches for substance misuse prevention, such as alcohol and tobacco prevention, has been conducted, few if any studies have focused on prescription opioid misuse prevention. Previous literature suggests that a comprehensive family-based approach can be effective in preventing substance misuse at the family-level. Considering the multiple age groups the sandwich generation cares for, the sandwich generation may have greater access to reaching multiple age groups to prevent prescription opioid misuse. Therefore, the purpose of this study is to use formative research findings to inform family-based approaches focused on preventing opioid misuse. A dual method approach that includes qualitative focus groups and quantitative surveys is used to explore adults’ perceptions of prescription opioid misuse, factors perceived as influencing opioid misuse prevention, and perceived predictors of prescription opioid misuse prevention. Participants were adults, 30 to 59 years of age, which is the average age range of the sandwich generation. Extension agents recruited focus group participants (n = 55) and Qualtrics recruited survey participants (n = 335) for this study. Focus group transcripts were coded based on common ideas that arose during the focus groups, previous literature, and the PRECEDE-PROCEED model. Focus group findings indicate that participants view the opioid crisis as a family problem, in which they have a role in preventing, and identified predisposing, reinforcing, and enabling factors that influence whether family members take a role in preventing prescription opioid misuse. Univariate frequencies and multiple linear regression analyses results of the survey data indicate that Theory of Planned Behavior determinants are predictive of the intention to talk about opioids with friends and family. In addition, comfort predicts intention to talk about opioids with friends and family, suggesting that Theory of Planned Behavior determinants and comfort predict intention. Extension agents, family life educators, and other community-health professionals can collaborate and use these findings to develop family-based approaches, such as family communication training and brief strategic family therapy, combined with community-based approaches such as motivational interviewing and media campaigns.