This study examines the relationship among neighborhood stressors, stress-buffering mechanisms, and likelihood of alcohol, drug, and mental health (ADM) disorders in adults from 60 US communities (n=12,716). Research shows that larger support structures may interact with individual support factors to affect mental health, but few studies have explored buffering effects of these neighborhood characteristics. We test a conceptual model that explores effects of neighborhood stressors and stress-buffering mechanisms on ADM disorders. Using Health Care for Communities with census and other data, we found a lower likelihood of disorders in neighborhoods with a greater presence of stress-buffering mechanisms. Higher neighborhood average household occupancy and churches per capita were associated with a lower likelihood of disorders. Cross-level interactions revealed that violence-exposed individuals in high crime neighborhoods are vulnerable to depressive/anxiety disorders. Likewise, individuals with low social support in neighborhoods with high social isolation (i.e., low-average household occupancy) had a higher likelihood of disorders. If replicated by future studies using longitudinal data, our results have implications for policies and programs targeting neighborhoods to reduce ADM disorders.