Aim: To determine the ecological processes and drivers of range collapse, population decline and eventual extinction of the steppe bison in Eurasia. Location: Siberia. Time period Pleistocene and Holocene. Major taxa studied Steppe bison (Bison priscus). Methods: We configured 110,000 spatially explicit population models (SEPMs) of climate–human–steppe bison interactions in Siberia, which we ran at generational time steps from 50,000 years before present. We used pattern-oriented modelling (POM) and fossil-based inferences of distribution and demographic change of steppe bison to identify which SEPMs adequately simulated important interactions between ecological processes and biological threats. These “best models” were then used to disentangle the mechanisms that were integral in the population decline and later extinction of the steppe bison in its last stronghold in Eurasia. Results: Our continuous reconstructions of the range and extinction dynamics of steppe bison were able to reconcile inferences of spatio-temporal occurrence and the timing and location of extinction in Siberia based on hundreds of radiocarbon-dated steppe bison fossils. We showed that simulating the ecological pathway to extinction for steppe bison in Siberia in the early Holocene required very specific ecological niche constraints, demographic processes and a constrained synergy of climate and human hunting dynamics during the Pleistocene–Holocene transition. Main conclusions: Ecological processes and drivers that caused ancient population declines of species can be reconstructed at high spatio-temporal resolutions using SEPMs and POM. Using this approach, we found that climatic change and hunting by humans are likely to have interacted with key ecological processes to cause the extinction of the steppe bison in its last refuge in Eurasia.