Two Amerindian demographic shifts are attributed to climate change in the northwest plains of North America: at ???11,000 calendar years before present (yr BP), Amerindian culture apparently split into foothills-mountains vs. plains biomes; and from 8,000-5,000 yr BP, scarce archaeological sites on the open plains suggest emigration during xeric "Altithermal" conditions. We reconstructed paleoclimates from stable isotopes in prehistoric bison bone and relations between weather and fractions of C4 plants in forage. Further, we developed a climate-change model that synthesized stable isotope, existing qualitative evidence (e.g., palynological, erosional), and global climate mechanisms affecting this midlatitude region. Our isotope data indicate significant warming from ???12,400 to 11,900 yr BP, supporting climate-driven cultural separation. However, isotope evidence of apparently wet, warm conditions at 7,300 yr BP refutes emigration to avoid xeric conditions. Scarcity of archaeological sites is best explained by rapid climate fluctuations after catastrophic draining of the Laurentide Lakes, which disrupted North Atlantic Deep Water production and subsequently altered monsoonal inputs to the open plains.