Minority stress has been posited as a framework to explain the health disparities seen in sexual minority youth, including lesbian, gay, bisexual (LGB+) youth. In the present study, psychological inflexibility was investigated as a moderator in the relationship between minority stress and two harmful youth outcomes: substance misuse and suicidality. Analyses showed significant interactions indicating moderating effects in the substance misuse models but not in the suicidality models. A positive direct effect of global psychological inflexibility on suicidality was also discovered. Analyses exploring the moderating effects of psychological inflexibility's sub-processes found that cognitive fusion and obstruction of valued living had significant, positive interactions with minority stress in relation to substance misuse. No moderating effects were found within models exploring the sub-processes on suicidality; however, positive direct effects were indicated between cognitive fusion and suicidality as well as between obstruction of valued living and suicidality. Overall, results suggest that psychological inflexibility is a promising moderator variable that could potentially be targeted via intervention in LGB + adolescents and therefore warrants further study with this population.