Permanent supportive housing (PSH) is the main approach advocated in Western countries for eradicating homelessness. Considering that PSH residents are not a homogeneous group and that their quality of life (QoL) and community integration (CI) might differ in this setting, improving our understanding of these residents’ profiles may help stakeholders formulate informed recommendations to improve PSH. This study identified PSH resident profiles based on their QoL, CI, and sociodemographic and clinical characteristics and associated these profiles with housing features and service use. A total of 308 PSH residents were recruited in Montreal (Canada) in 2020–2022. Structured interviews were conducted. PSH resident profiles were produced with cluster analysis and subsequently compared using chi-square, Fisher’s, and t-tests, taking into account housing features and service use. Three PSH resident profiles were found. Profile 1 residents (22% of the sample) had low QoL and CI, were younger, and had major social and health issues and unmet needs. Showing moderate QoL and CI, Profile 2 residents (27%) were more educated, had little foster care history, were older on their first homelessness episode, and had few co-occurring MD-SUD. Profile 3 residents (51%) had the best QoL and CI and mostly included men with little education, affected by co-occurring MD-SUD and satisfied with services. More intensive housing support and care coordination may be recommended for Profile 1 PSH residents in response to their diverse needs. Work integration may be beneficial to Profile 2 residents, with programs such as Individual Placement and Support, along with increased rehabilitation activities. A better integration of MD-SUD treatments may be promoted for Profile 3 residents. Considering most PSH residents had multiple health issues and unmet needs, satisfaction with care could be monitored better, as it was found to be a key variable in measuring care adequation.