Pathways to extinction start long before the death of the last individual. However, causes of early stage population declines and the susceptibility of small residual populations to extirpation are typically studied in isolation. Using validated process-explicit models, we disentangle the ecological mechanisms and threats that were integral in the initial decline and later extinction of the woolly mammoth. We show that reconciling ancient DNA data on woolly mammoth population decline with fossil evidence of location and timing of extinction requires process-explicit models with specific demographic and niche constraints, and a constrained synergy of climatic change and human impacts. Validated models needed humans to hasten climate-driven population declines by many millennia, and to allow woolly mammoths to persist in mainland Arctic refugia until the mid-Holocene. Our results show that the role of humans in the extinction dynamics of woolly mammoth began well before the Holocene, exerting lasting effects on the spatial pattern and timing of its range-wide extinction.