OBJECTIVE: To investigate the association of both individual and combined healthy lifestyle factors with the risk of all-cause mortality among patients with osteoarthritis (OA). DESIGN: Prospective population-based cohort study. SETTING: UK biobank and US National Health and Nutrition Examination Survey (US NHANES, 2007-2018) PARTICIPANTS: 104, 142 UK participants with OA aged 39-72 years and 3, 472 US participants with OA aged 20-80 years. EXPOSURES: Individual healthy lifestyle factors and a combined healthy lifestyle score were constructed from body mass index (BMI) and self-reported information on diet, sleep duration, physical activity, sedentary time, social connection, smoking and alcohol drinking. MAIN OUTCOME MEASURES: All-cause mortality was the primary outcome in both studies. Secondary outcomes included cause-specific mortalities (cardiovascular, cancer, digestive and respiratory). Hazard ratios were adjusted for age, sex, economic situation, race, education and employment (UK biobank only). RESULTS: UK Biobank documented 9,914 deaths during a median follow-up of 12.7 years, and US NHANES documented 463 deaths during a mean follow-up of 6.01 years. For all-cause mortality using restricted cubic spline graph (RCS) models, sleep duration had a U-shaped (with a nadir at 7 hours/day), moderate physical activity (MPA) had an L-shaped (with a turning point at 550 minutes/week), while BMI, vigorous physical activity (VPA) and sedentary time had J-shaped (with turning points at 28 kg/m2, 240 minutes/week and 5 hours/day, respectively) associations in the UK biobank. Similar results were observed in US NHANES. In multivariable Cox models, each healthy lifestyle factor was significantly associated with all-cause mortality (hazard ratio [HRs] range 0.49 to 0.84 for UK biobank, and 0.26 to 0.73 for US NHANES), and HRs (95% CI) for associations with combined healthy lifestyle score (scoring 6-8 vs. 0-2) were 0.38 (0.35, 0.41) in UK biobank and healthy lifestyle score (scoring 5-7 vs. 0-1) were 0.20 (0.13, 0.31 ) in US NHANES for all-cause mortality. The results for cause-specific mortality were largely similar and consistent across two cohorts. CONCLUSIONS: The nonlinear relationships suggested patients with OA had the lowest risk of all-cause mortality when BMI was 28 kg/m2, sleep was 7 hours/day, VPA was 240 minutes/week, sedentary time was less than 5 hours/day, MPA was more than 550 minutes/week. The newly constructed healthy lifestyle score for OA population was associated with a significantly lower risk of all-cause mortality.