Background <p>Social isolation and health impacting factors (used to calculate a unhealth risk score) pose significant public health challenges globally. This study aims to investigate the associations between social isolation, unhealthy risk score, and the risk of mortality among Chinese and American older adults.</p> Methods <p>Seven thousand nine hundred seventy-three Chinese older adults from the China Health and Retirement Longitudinal Study (CHARLS) and 6,207 American older adults from the Health and Retirement Study (HRS) were analyzed. The exposures were social isolation and an unhealthy risk score derived from health-impacting factors. Social isolation was evaluated based on the number of household members, frequency of social activities, contact frequency with others, and marriage status. The unhealthy risk score was established based on the Cox regression coefficients of health impacting factors and age. The health impacting factors include hand grip strength (HGS), blood pressure, waist circumference (WC), and pulmonary function, smoking status, alcohol consumption, blood glucose, sleep, balance ability and diet. The Cox regression model was employed to analyze the effects of social isolation and unhealthy risk score on all-cause mortality. Machine learning was used to identify the most important health impacting factor among participants with and without social isolation.</p> Results <p>Nine hundred ten death cases were recorded in the CHARLS cohort during a mean follow-up of 8.18 years, and 2,182 death cases were documented in the HRS cohort during a mean follow-up of 10.84 years. Social isolation and unhealthy risk score showed significant associations with an increased risk of mortality in both CHARLS cohorts (HR 1.42, 95% CI 1.24 ~ 1.64) and HRS (hazard ratio (HR), 1.54, 95% confidence interval (CI) 1.42 ~ 1.68). Unhealthy risk score showed an increased association with all-cause mortality in CHARLS cohort (HR and 95% CI, 2.11 (1.77,2.52)) and HRS cohort (HR and 95% CI, 1.55 (1.41,1.71)). Social isolation and unhealthy risk score showed significant joint adverse impact on all-cause mortality. Smoking status, pulmonary function, blood pressure, and HGS were the primary health impacting factor in participants with and without social isolation.</p> Conclusions <p>Social isolation and unhealthy risk score are each associated with an increased risk of all-cause mortality. The combination of unhealthy risk score and social isolation was strongly associated with elevated mortality risk. The most important health impacting factor related with all-cause mortality in participants with social isolation were smoking status, pulmonary function, blood pressure, and HGS. The findings highlight the importance of promoting initiatives to address social isolation and unhealthy factors.</p>