Kratom is federally unregulated and is marketed as an opioid alternative despite limited evidence and known negative effects. Disparities in associations between opioid and kratom use may be partly attributed to race/ethnicity and sexual orientation given differences in marketing, use motives, and prescriber practices. Data: 2021 nationally representative National Survey on Drug Use and Health among individuals aged 18 + . We used weighted logistic regression analyses to assess race/ethnicity and sexual orientation as moderators of associations between past-year opioid (1) use (total sample, n = 44,877) and (2) misuse and use disorder (among those with past-year opioid use, n = 10,398) and the outcome of kratom use (lifetime, past year). 26.76% reported past-year opioid use, and among those, 12.20% and 7.54% reported past-year opioid misuse and use disorder, respectively; 1.72% and 0.67% had lifetime and past-year kratom use, respectively. Opioid use was positively associated with lifetime (aOR = 2.69, 95%CI = 1.98, 3.66) and past-year (aOR = 3.84, 95%CI = 2.50, 5.92) kratom use; associations among non-Hispanic Black and Hispanic (vs. non-Hispanic White) participants were weaker (p < 0.01). Among participants reporting past-year opioid use, misuse and use disorder were positively associated with lifetime (aORmisuse = 2.46, 95%CI = 1.60, 3.78; aORuse disorder = 5.58, 95%CI = 2.82, 11.04) and past-year (aORmisuse = 2.40, 95%CI = 1.26, 4.59; aORuse disorder = 3.08, 95%CI = 1.48, 6.41) kratom use; among bisexual (vs. heterosexual) participants, opioid use disorder was associated with a lower probability of lifetime kratom use (p < 0.01). We observed positive associations between opioid and kratom use, with potential disparities among certain racial/ethnic and sexual orientation groups. Research should examine the mechanisms contributing to these differences to inform prevention and intervention efforts.