Background: The COVID-19 pandemic has seen a considerable expansion in the way work settings are structured with a continuum emerging between working fully in-person and from home. The pandemic has also exacerbated many risk factors for poor mental health in the workplace, especially in public-facing jobs. Therefore, we sought to test the potential relationship between work setting and self-rated mental health. Methods: We modeled the association of work setting (only working from home, only in-person, hybrid) on self-rated mental health (Excellent/Very Good/Good vs. Fair/Poor) in an online survey of Canadian workers during the 3rd wave of COVID-19. Mediating effects of vaccination, masking, and distancing were explored due to the potential effect of COVID-19 related worries on mental health among those working in-person. Results: Among 1,576 workers, most reported hybrid work (77.2%). Most also reported good self-rated mental health (80.7%). Exclusive work from home (aOR: 2.79, 95%CI:1.90,4.07) and exclusive in-person work (aOR: 2.79, 95%CI: 1.83,4.26) were associated with poorer self-rated mental health than hybrid work. Vaccine status mediated only a small proportion of this relationship (7%), while masking and physical distancing were not mediators. Conclusion: Hybrid work arrangements were associated with positive self-rated mental health. Compliance to vaccination, masking, and distancing did not meaningfully mediate this relationship.