ObjectivesTo examine independent and interactive associations of physical activity and diet with all-cause, cardiovascular disease (CVD) and physical activity, diet and adiposity-related (PDAR) cancer mortality.MethodsThis population-based prospective cohort study (n=346 627) is based on the UK Biobank data with linkage to the National Health Service death records to 30 April 2020. A left-truncated Cox proportional hazards model was fitted to examine the associations between exposures (self-reported total moderate-to-vigorous intensity physical activity (MVPA), vigorous-intensity physical activity (VPA) and a diet quality index (score ranged 0–3)) and outcomes (all-cause, CVD and PDAR cancer mortality).ResultsDuring a median follow-up of 11.2 years, 13 869 participants died from all causes, 2650 from CVD and 4522 from PDAR cancers. Compared with quartile 1 (Q1, 0–210 min/week), Q2–Q4 of MVPA were associated with lower risks of all-cause (HR ranged from 0.87 (95% CI: 0.83 to 0.91) to 0.91 (95% CI: 0.87 to 0.96)), CVD (HR ranged from 0.85 (95% CI: 0.76 to 0.95) to 0.90 (95% CI: 0.81 to 1.00)) and PDAR cancer mortality (HR ranged from 0.86 (95% CI: 0.79 to 0.93) to 0.94 (95% CI: 0.86 to 1.02)). Compared with no VPA, any VPA was associated with lower risk for all-cause and CVD mortality (HR ranged from 0.85 (95% CI: 0.80 to 0.89) to 0.88 (95% CI: 0.84 to 0.93) and from 0.75 (95% CI: 0.68 to 0.83) to 0.90 (95% CI: 0.80 to 1.02), respectively). Although not reaching statistical significance for all-cause and CVD mortality, being in the best dietary category (diet quality index=2–3) was associated with a reduction in PDAR cancer mortality (HR=0.86, 95% CI: 0.78 to 0.93). No additive or multiplicative interactions between physical activity categories and dietary quality was found. When comparing across physical activity and diet combinations, the lowest risk combinations consistently included the higher levels of physical activity and the highest diet quality score.ConclusionsAdhering to both quality diet and sufficient physical activity is important for optimally reducing the risk of mortality from all causes, CVD and PDAR cancers.