Current studies on cultigens emphasize the protracted and intimate human interactions with wild species that defined paths to domestication and, for certain plants, profoundly impacted humanity1,2. Tobacco (Nicotiana) is one such plant. Tobacco arguably has had more impact on global patterns in history than any other psychoactive substance, but how deep its cultural ties trace back is widely debated. Adding to the puzzle is whether the distribution of tobacco in North America occurred naturally or if humans themselves were responsible for its expansion across the continent3. Archaeological excavations at the Wishbone site, directed at the hearth-side activities of the early inhabitants of North America’s desert west, have uncovered evidence for tobacco approximately 12,300 years ago, 9,000 years earlier than previously documented4. Here we detail the preservation context of the site, discuss its cultural affiliation, and consider the ways that the tobacco may have been used. Researchers have long suspected that human use extends earlier in time than can been readily demonstrated by such fragile remains3–7, so the finding reinvigorates research on the driving cultural forces behind tobacco’s use, cultivation, and subsequent domestication. This has implications for our understanding of deep-time human use of plant intoxicants, the intersection of non-food plant domestication with that of food crops, and the trajectory of selective, potentially independent, interactions with tobacco from a broad cultural milieu in ancient North America to a place of worldwide cross-cultural significance.