Despite public health efforts, use of legal substances such as cigarettes, cannabis and e-cigarettes are common in Canada. Most policies focus on individual level factors, which do not account for possible influences of the environments to which people belong (i.e., neighborhoods). This study aimed to identify neighborhood-level risk factors for use of cigarettes, cannabis and e-cigarettes in the Canadian Partnership for Tomorrow's Health cohort. Participants completed questionnaires on demographics and health behaviors including recent (30-day) use of cigarettes, cannabis and e-cigarettes. Geospatial neighborhood-level measures: deprivation, gentrification, household security, labor force participation, immigration and visible minority proportion were linked via postal codes. Regression models were built to understand associations between substance use and neighborhood factors. Neighborhood material deprivation, social deprivation, and household insecurity were positively associated with odds of using cigarettes, cannabis, and e-cigarettes. Odds of using these substances was higher for participants living in gentrified neighborhoods. Lower odds of cigarette, cannabis, and e-cigarette use were found for participants living in neighborhoods with a high proportion of recent immigrants and/or visible minorities. Evidence from this study suggests interventions aimed at reducing or preventing substance use should be multidimensional, encompassing strategies directed at both individuals and neighborhoods.