Research examining how youth substance use is associated with both proximal microsystemic processes (interactions with family members) and distal macrosystemic conditions (rurality) is limited. To address this gap, a person-/variable-centered approach was used to: (1) identify latent profiles of family risk and protective factors for substance use, (2) test profile membership as a predictor of lifetime and 30-day substance use, (3) test rurality, as measured by school geographic location, as a predictor, and (4) explore interaction effects between profile membership and rurality. Youth (N = 9,104; 53% female) residing in a state in the southeastern U.S. completed a statewide substance abuse and risk behavior survey including questions about family risk and protective factors and substance use behaviors. Using latent profile analysis to identify subgroups of participants with similar means and variances on the family factors, four latent profiles emerged. Risk of 30-day and lifetime substance use varied across profiles, with the profile characterized by high family-level protective factors and low family-level risk factors indicating the lowest risk for substance use. Urban youth had increased odds of reporting lifetime marijuana use compared to suburban youth; however, geographic location did not appear to confer significantly increased or decreased risk across other substances. No significant interaction results were found. These results emphasize the importance of family functioning on substance use regardless of geographic location, and that evidence-based prevention programming that reduces family risk, strengthens family protection, and is accessible to all types of communities is important to reducing or delaying substance use among youth.