Canadian young adults who identify as Two Spirit, lesbian, gay, bisexual, trans, queer, intersex (2SLGBTQI+) have higher smoking rates compared to their straight cisgender counterparts. One of the reasons for this trend is the perceived social acceptability of smoking and how it relates to stress, mental health and social connections. A sequential mixed-methods study was conducted with qualitative focus groups, followed by quantitative survey data collection starting in the spring of 2020, examining perceptions of both smoking and vaping. Results demonstrate higher social acceptability of vaping compared to smoking in the study sample. Qualitative results showed a strong link between the higher acceptability of smoking and vaping with coping and social connections. Quantitative results indicated that higher smoking acceptability was more common among those who currently smoke, currently vape, are younger, live in smaller cities, identify as a person of color, with variation by gender and sexual orientation; vaping was found to be more acceptable among those who currently smoke, currently vape, were younger participants, and have some post-secondary education. This research is important for the development of prevention and cessation programs in addressing both the negative and positive dimensions affecting smoking among 2SLGBTQI+young adults.