Homeless individuals represent a disadvantaged and marginalised group who experience increased rates of physical illness as well as mental and substance use disorders. Compared to stably housed individuals, homeless adults with mental disorders use hospital emergency departments and other acute health care services at a higher frequency. Housing First integrates housing and support services in a client-centred model and has been shown to reduce acute health care among homeless populations. The present analysis is based on participants enrolled in the Vancouver At Home Study (n = 297) randomised to one of three intervention arms (Housing First in a ‘congregate setting’, in ‘scattered site’ [SS] apartments in the private rental market, or to ‘treatment as usual’ [TAU] where individuals continue to use existing services available to homeless adults with mental illness), and incorporates linked data from a regional database representing six urban emergency departments. Compared to TAU, significantly lower numbers of emergency visits were observed during the post-randomisation period in the SS group (adjusted rate ratio 0.55 [0.35,0.86]). Our results suggest that Housing First, particularly the SS model, produces significantly lower hospital emergency department visits among homeless adults with a mental disorder. These findings demonstrate the potential effectiveness of Housing First to reduce acute health care use among homeless individuals and have implications for future health and housing policy initiatives.