The biological and behavioural mechanisms linking psychological distress to excess mortality in people living with and beyond cancer (LWBC) remain poorly understood. In this multi-cohort study, we examine the associations between psychological distress and both cancer-specific and all-cause mortality in individuals living with and beyond cancer (LWBC), and assess the potential mediating roles of inflammation and health behaviours. The primary analysis includes 13,349 adults from the UK Biobank (2006-2021), with replication in 5,739 participants from the Finnish Public Sector study (2000-2018). Psychological distress is associated with an increased risk of all-cause mortality (pooled adjusted risk ratio (RR), 1.54, 95% confidence interval (CI), 1.37-1.74) and cancer mortality (pooled RR, 1.57; 95% CI, 1.37-1.79). Systemic inflammation explains up to 18.6% of these associations, whereas diet, alcohol consumption, and body mass index do not mediate these relationships. Evidence for mediation by other health behaviours is inconsistent. While adjustment for cancer stage attenuates the distress-mortality link by up to 25%, psychological distress remains a robust predictor of both all-cause and cancer mortality. These findings suggest that psychological distress is an independent predictor of mortality risk in people LWBC, partially attributable to elevated levels of systemic inflammation.