In the Tapajós River region of the Brazilian Amazon, mercury (Hg) is a prevalent contaminant in the aquatic ecosystem. Few studies have used comprehensive chronological analyses to examine the combined effects of environmental and anthropogenic factors on Hg accumulation in sediments. Total mercury (THg) content was measured in sediments from eight floodplain lakes and Pb210 isotope analysis was used to develop a timeline of THg accumulation. Secondary data representing environmental and anthropogenic factors were analyzed using geo-spatial analyses. These include land-cover change, hydrometeorological time-series data, lake morphology, and watershed biophysical characteristics. The results indicate that THg accumulation and sedimentation rates have increased significantly at the surface of most sediment cores, sometimes doubling since the 1970s. Human-driven land-cover changes in the watershed correspond closely to these shifts. Tropical deforestation enhances erosion, thereby mobilizing the heavy metal that naturally occurs in soils. Environmental factors also contribute to increased THg content in lacustrine sediments. Climate shifts since the 1980s are further compounding erosion and THg accumulation in surface sediments. Furthermore, variations in topography, soil types, and the level of hydrological connectivity between lakes and the river explain observed variations in THg fluxes and sedimentation. Although connectivity naturally varies among sampled lakes, deforestation of sensitive floodplain vegetation has changed lake-river hydrology in several sites. In conclusion, the results point to a combination of anthropogenic and environmental factors as determinants of increased THg accumulation in tropical floodplain sediments in the Tapajós region.