The Lake Baikal region has been inhabited by modern humans since the Upper Paleolithic, though the precise history of its inhabitants over this long period is still largely unknown. Here we report genome-wide data from 19 Upper Paleolithic to Early Bronze Age individuals from this region. An Upper Paleolithic genome shows a direct link with the First Americans by sharing the admixed ancestry which gave rise to all non-Arctic Native Americans. We demonstrate the genomic transition between Early Neolithic and Bronze Age Baikal groups as the result of prolonged admixture throughout the eighth millennium BP. In addition, we detect genetic interactions with western Eurasian steppe populations and reconstruct Yersinia pestis genomes from two Early Bronze Age individuals without west Eurasian ancestry. Overall, our study demonstrates the most deeply divergent connection between Upper Paleolithic Siberians and First Americans and reveals high human and pathogen mobility across Eurasia during Bronze Age.