Knee symptomatic osteoarthritis (SxOA) was associated with all-cause mortality. Walking disability and NSAIDs use have been postulated as potential mechanisms linking knee SxOA to all-cause mortality. Data were collected on ability of walking for 1 kilometer and use of NSAIDs at baseline and death information at follow-up. Subjects with knee SxOA were identified if at least one knee had both radiographic OA and pain. We first fitted a Cox proportional hazards model to examine the relation of knee SxOA to the risk of all-cause mortality. We then used marginal structural models to decompose total effect of knee SxOA on all-cause mortality into indirect and direct effects via walking disability and use of NSAIDs, respectively. Among 1025 subjects, 99 died over 8 years of follow-up. A multivariable adjusted hazard ratio of mortality for SxOA was 1.98 (95% CI: 1.09-3.62). The indirect effect of knee SxOA on all-cause mortality through either a walking disability or NSAIDs use was 1.92 (95% CI: 0.86-4.26) and 1.45 (95% CI: 0.72-2.92), respectively. The corresponding direct effect was 1.08 (95% CI: 0.55-1.12) and 1.35 (95% CI: 0.75-2.44). In this population-based cohort study, high all-cause mortality from knee SxOA was mediated mainly through a walking disability.