This study aims to examine the associations between midlife Life’s Simple 7 (LS7) status, psychosocial health (social isolation and loneliness), and late-life multidimensional frailty indicators, and to investigate their synergistic effect on frailty. We used cohort data from the UK Biobank. Frailty was assessed using physical frailty phenotype, hospital frailty risk score, and frailty index. Cox proportional-hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) on the association between the LS7 score, psychosocial health, and frailty. For the association of LS7 with physical and comprehensive frailty, 39,047 individuals were included. After a median follow-up of 9.0 years, 1329 (3.4%) people were identified with physical frailty, and 5699 (14.6%) with comprehensive frailty. For the association of LS7 with hospital frailty, 366,570 people were included. After a median follow-up of 12.0 years, 18,737 (5.1%) people were identified with hospital frailty. Compared to people with a poor LS7 score, those with an intermediate (physical frailty: 0.64, 0.54–0.77; hospital frailty: 0.60, 0.58–0.62; and comprehensive frailty: 0.77, 0.69–0.86) and optimal LS7 score (physical frailty: 0.31, 0.25–0.39; hospital frailty: 0.39, 0.37–0.41; and comprehensive frailty: 0.62, 0.55–0.69) were associated with a lower risk of frailty. Poor psychosocial health was associated with an increased risk of frailty. People who had a poor psychosocial status and poor LS7 score had the highest risk of frailty. A better LS7 score in midlife was associated with a reduced risk of physical, hospital, and comprehensive frailty. There was a synergistic effect of psychosocial status and LS7 on frailty.