SummaryBackgroundPhysical frailty is a state of increased vulnerability to stressors and is associated with serious health issues. However, how frailty affects and is affected by numerous other factors, including mental health and brain structure, remains underexplored. We aimed to investigate the mutual effects of frailty and health using large, multidimensional data.MethodsFor this population-based study, we used data from the UK Biobank to examine the pattern and direction of association between physical frailty and 325 health-related measures across multiple domains, using linear mixed-effect models and adjusting for numerous confounders. Participants were included if complete data were available for all five indicators of frailty, all covariates, and at least one health measure. We further examined the association between frailty and brain structure and the role of this association in mediating the relationship between frailty and health outcomes.Findings483 033 participants aged 38–73 years were included in the study at baseline (between Dec 19, 2006, and Oct 1, 2010); at a median follow-up of 9 years (IQR 8–10), behavioural data were available for 46 501 participants and neuroimaging data for 40 210 participants. The severity of physical frailty was significantly associated with decreased cognitive performance (Cohen’sd=0·025–0·162), increased early-life risks (d=0·026–0·111), unhealthy lifestyle (d=0·013–0·394), poor physical fitness (d=0·007–0·668), increased symptoms of poor mental health (d=0·032–0·607), severe environmental pollution (d=0·013–0·064), and adverse biochemical markers (d=0·025–0·198). Some associations were bidirectional, with the strongest effects on mental health measures. The severity of frailty correlated with increased total white matter hyperintensity and lower grey matter volume, particularly in subcortical regions (d=0·027–0·082), which significantly mediated the association between frailty and health-related outcomes, although the mediated effects were small.InterpretationPhysical frailty is associated with diverse unfavourable health-related outcomes, which can be mediated by differences in brain structure. Our findings offer a framework for guiding preventative strategies targeting both frailty and psychiatric disorders.