A multiproxy study from Sweeton Pond, Ozark County, Missouri, USA, provides a high-resolution 1900-year-long history of vegetation and fire in the southern Missouri Ozarks, where the modern vegetation is oak-hickory (Quercus-Carya) forest. Pollen and charcoal data are compared with dendroecological data to assess how climate and fire shaped local vegetation history. Land use, particularly by the Osage tribe of Native Americans, is assessed from historical and archaeological records. Three cultural periods are superimposed on the paleoenvironmental history: (1) The Pre-Osage period, ending ~1500 CE, was characterized by open oak-hickory forest and frequent low-severity fires, suggesting interannual climate variability as a driver of vegetation and fire occurrence. At ~1360 CE, mesic tree species began to expand, while fire frequency remained low. (2) The Osage period (~1500–1820 CE) was characterized by the continued expansion of mesic, fire-sensitive species, especially elm (Ulmus), in conjunction with cool, effectively wet conditions in the southern Missouri Ozarks. Despite climate conditions less favorable for fire, Osage expansion in the region was accompanied by increased fire and fire-dependent shortleaf pine (Pinus echinata). The expansion of both fire-sensitive and fire-dependent taxa coincident with Osage occupation suggests that anthropogenic fire and land use was local in nature and increased landscape heterogeneity prior to Euro-American settlement. (3) The Euro-American period (since ~1820 CE) was characterized by increased disturbance pollen types (e.g. Ambrosia-type) at the expense of shortleaf pine pollen, resulting from increased settlement size and extensive agricultural and logging activities. During this period, forest clearance led to fuel fragmentation, reducing fire activity; after 1920 CE, fire was actively suppressed.