The relationships between chronic exposure to wildfire smoke PM2.5 (particulate matter with aerodynamic diameter of ≤2.5 μm) and mortality remain poorly understood, with causal evidence being particularly scarce. In this ecological study, we used a doubly robust method, incorporating flexible generalized propensity score estimation that captured potential nonlinearity and interactions among confounders and relaxed the distribution form assumption for exposure, to estimate the effects of annual exposure to wildfire smoke PM2.5 on all-cause and cause-specific mortality in the contiguous United States from 2006 to 2020. We found that wildfire smoke PM2.5 was associated with increased mortality rate for all studied outcomes, except for deaths from transport accidents or falls, which served as negative outcome controls. Wildfire smoke PM2.5 was responsible for ~24,100 all-cause deaths per year in the contiguous United States. The exposure-response curve for all-cause mortality increased monotonically, with no evidence of a “safe” threshold. Among the six cause-specific outcomes, mortality from neurological disease showed the greatest increase per 0.1 μg/m3 increase in smoke PM2.5 exposure. Our study provided robust evidence for the chronic effect of wildfire smoke PM2.5 on mortality, underscoring the urgent need for targeted measures to mitigate the substantial and escalating burden of wildfires.