ABSTRACT Background: Bisexual and mostly heterosexual women report higher substance use than exclusively heterosexual or lesbian women. In sexual minority men, sex-linked substance use (SLSU) can increase risk for substance use problems; equivalent research in women is lacking. Objectives: To test if sexual excitation and inhibition mediate the association between sexual minority status and women’s SLSU. Methods: We surveyed a convenience sample of 595 undergraduate women who identified as exclusively heterosexual (n = 499), mostly heterosexual (n = 59), or bisexual (n = 37). Participants reported on their last month use of alcohol, cannabis, and other drugs (e.g., cocaine) in sexual and non-sexual contexts, and symptoms of alcohol and non-alcohol drug use disorders (e.g., withdrawal symptoms). Drug use symptoms were collapsed across non-alcohol substances. We used structural equation modeling to test serial mediations of women’s SLSU and overall drug and alcohol use. Results: Bisexual and mostly heterosexual women reported higher cannabis use (η2 = 0.030) and drug use disorder symptoms (η2 = 0.050) than heterosexual women. Mostly heterosexual women’s SLSU was a stronger predictor of alcohol use (η2 = 0.019) and binge drinking frequency (η2 = 0.015) than for other orientation groups. Bisexual and mostly heterosexual women’s higher sexual excitation predicted their higher SLSU, which in turn predicted higher cannabis use frequency and drug use disorder symptoms. However, sexual inhibition failed to mediate either SLSU or overall substance use. Conclusion: These findings point to SLSU as a mechanism by which sexual minority women may experience disparities in substance use related harms.