This research investigated the effects of social isolation on frailty and health outcomes and tested whether these associations varied across different levels of frailty. We performed a multivariate analysis of data from the first wave of the FRéLE study among 1,643 Canadian older adults aged 65 years and over. We assessed social isolation using social participation, social networks, and support from various social ties, namely, friends, children, extended family, and partner. Frailty predicted disability, comorbidity, depression, and cognitive decline. Less social participation was associated with IADLs, depression, and cognitive decline. The absence of friends was associated with depression and cognitive impairment. Less social support from children and partner was related to comorbidity, depression, and cognitive decline. Overall, social isolation is linked to mental health, rather than physical health. The associations of having no siblings, receiving less support from friends, and participating less in social activities with ADL limitations, depression, and cognitive decline were higher among frail than pre-frail and robust older adults. This study corroborates the pivotal role of social connectedness, particularly the quality of relationships, on the mental health of older adults. Public health policies on social relationships are paramount to ameliorate the health status of frail older adults.