The current study aims to examine the direct effect of perceptions of neighborhood safety on youth substance use (i.e., tobacco, alcohol, cannabis, other drugs). The study also aims to examine whether the risk pathway operates indirectly through self-esteem, and whether adult or peer support moderates this effect. Using an archival dataset, participants included 8461 youth (80.8% white, 54.2% female) between grades 6–10 completed measures on lack of neighborhood safety, self-esteem, substance use, and social support from parents, peers, and teachers. After controlling for demographic variables, lack of neighborhood safety was associated with greater substance use, with the risk pathway operating indirectly through self-esteem. Support from parents and teachers/staff were found to moderate the risk pathway, such that the effect of neighborhood safety on substance use decreased with increased support. These moderating effects were dependent on the type of substance being used: Based on the study findings, targeting self-esteem and fostering adult support systems may help reduce the negative effect perceptions of lack of neighborhood safety have on youth substance use outcomes.