Background: Whether parental permission of alcohol and other drug use in a home environment is protective against substance-related negative outcomes remains controversial. We investigated substance use at home, with or without parental knowledge, and its association with substance-related consequences. Methods: The sample consisted of 21,207 U.S. students in the 6th to 12th grades surveyed between 2009 and 2017. Substance use patterns and rates of negative outcomes were analyzed by comparing groups of participants who had not used at home, or had used at home with and/or without parental knowledge. Results: Adolescents who used substances at home without parental knowledge used alcohol and substances in greater amounts, and tended to have more negative outcomes than those who did not. Students who had not used at home or had used only with parental knowledge tended to have lower levels of use and negative outcomes. Conclusions: Using at home without parental knowledge was a consistent risk factor for substance-related negative outcomes. These results highlight the importance of screening adolescents for the use of alcohol or drugs in the home without parental knowledge, as well as attempting to prevent substance use in the household.