Heightened rates of prescription opioid misuse have been observed among sexual minority (SM) compared with heterosexual populations. In addition, depression and suicidal ideation are risk factors for misuse, and they are also elevated among SM populations. The purpose of this analysis was to examine whether depression and suicidal ideation attenuate disparities in prescription opioid misuse among SM adults. Data came from a publicly available, nationally representative data set, the National Survey on Drug Use and Health, 2015-2018. Among adults, survey-weighted logistic regression was used to assess the relationship between sexual orientation and past-year opioid misuse adjusting for demographics and either past-year major depressive episode or suicidal ideation. Probabilities of prescription opioid misuse were also assessed under counterfactual rates of depression and suicidal ideation. Analyses were stratified by sex. Among participants in the analytic sample ( = 169,759; SM = 11,268), 9254 (5.5%) reported past-year prescription opioid misuse. The overall rate of opioid misuse decreased from 6.2% in 2015 to 4.6% in 2018. The association between sexual orientation and opioid misuse was attenuated downward for gay men, lesbian women, and bisexual individuals (men and women) after adjusting for either major depressive episode or suicidal ideation, but opioid misuse remained higher among most SM groups. In addition, rates of opioid misuse were found to be lower in counterfactual analyses with a nearly 2.5- and 4-fold decrease in depression and suicidal ideation among gay men and bisexual women, respectively. Efforts to reduce disparities in depression and suicidal ideation affecting SM individuals may reduce disparities in prescription opioid misuse affecting this population.