Loneliness and lack of social connection are widespread and negatively affect physical and mental health and well-being. Data are limited for persons disproportionately affected by social disconnection, especially those who do not identify as heterosexual and cisgender. Using data from the 2022 Behavioral Risk Factor Surveillance System in 26 U.S. states, CDC examined associations of loneliness and lack of social and emotional support to mental health variables. Prevalence estimates for the mental health variables were significantly higher among adults who reported loneliness and lack of social and emotional support than among those adults who did not. The prevalence of loneliness was highest among respondents who identified as bisexual (56.7%) and transgender (range = 56.4%-63.9%). Prevalence of lack of social and emotional support was highest among those who identified as transgender female (44.8%), transgender gender nonconforming (41.4%), and those with household income below $25,000 (39.8%). Prevalences of stress, frequent mental distress, and history of depression were highest among bisexual (34.3%-54.4%) and transgender adults (36.1%-67.2%). Addressing the threat to mental health among sexual and gender minority groups should include consideration of loneliness and lack of social and emotional support. Providing access to health services that are affirming for sexual and gender minority groups and collecting data to address health inequities might help improve the delivery of culturally competent care.