Purpose: The 2016 U.S. election significantly changed the political landscape for sexual and gender minority (SGM) individuals. The current study assessed the consequences of the election and transition to a new overtly discriminatory administration on the health-related quality of life of SGM adults compared with their cisgender and heterosexual counterparts. Methods: The study used repeated cross-sectional data from the 17 states that administered the sexual orientation and gender identity module in the 2015 and 2018 Behavioral Risk Factor Surveillance System surveys. The sample included 268,851 adult respondents: 12,006 SGM adults (5.35%) and 256,845 cisgender and heterosexual adults (94.65%). Outcomes were frequent (≥14 days in the last month) physical distress, mental distress, limited activity, and/or fair/poor general health. Difference-in-differences estimates were calculated from logistic regression models, controlling for sociodemographic, health care coverage, and chronic medical condition confounders. Results: Compared with the cisgender and heterosexual population, frequent mental distress among SGM adults increased by 5% points, corresponding to a relative increase of 32.5% (p < 0.001) from 2015. Rates of frequent physical distress, limited activity, and fair/poor general health were not significantly altered between the two populations. Gender minority adults were most negatively affected with a relative increase in frequent mental distress of 117.5% (p < 0.001). Conclusions: The 2016 U.S. election and administration changeover were associated with a substantial increase in the proportion of SGM adults reporting frequent mental distress. These data provide empirical evidence as to the psychological effects of an abrupt political realignment on SGM mental health.