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We examine the annual, seasonal, monthly, and diurnal climate responses to the land use change (LUC) in eastern United States and Cuba during four epochs (1650, 1850, 1920, and 1992) with ensemble simulations conducted with the RegCM4 regional climate model that includes the Biosphere Atmosphere Transfer Scheme (BATS1e) surface physics package (Dickinson et al., 1993). We derived the land use (LU) data sets by harmonizing a previous reconstruction (Steyaert & Knox, 2008) with updated observations and modeled potential vegetation. The eight‐member ensembles for each epoch were driven with randomly perturbed 1990–2002 atmospheric boundary conditions derived from the National Center for Environmental Prediction global reanalysis. LUC induces statistically significant climate responses across all epochs; the largest changes occur between 1850 and 1920 with the widespread conversion of forests in the United States and forests, grassland, and woody wetlands in Cuba to agriculture. The atmospheric feedback from the aggregated grid‐cell responses attributed to physical and biophysical parameters in BATS1e alters the circulation in the lower atmosphere, thereby propagating the LUC regionally. Depending on the season and location, the altered circulation reinforces, attenuates, or has little effect on surface responses. Relative to pre‐settlement (1650), the 1992 LU produces colder mean annual air temperature (−0.09 ± 0.16 °C) and increased precipitation (0.08 ± 0.09 mm day−1) over the United States, warmer (0.08 °C) and wetter (0.03 mm day−1) conditions over Florida, and warming (0.32 °C) and drying (−0.03 mm day−1) over Cuba, indicating that LUC has played a varying role in climate change over the region. Plain Language Summary: We apply a regional climate model to evaluate the climate responses to land use (LU) and land use change (LUC) in the eastern United States and Cuba over four epochs 1650, 1850, 1920, and 1992. We used multiple simulations to create ensembles to isolate the climate responses from intrinsic variability in the model. We find that LUC alters regional circulation and leads to varying changes in temperature, precipitation, and the surface energy and water balances. From 1650 to 1992, LUC primarily associated with agriculture induced cooler temperatures and greater precipitation over the eastern United States, warmer and wetter conditions over Florida, and warmer and drier conditions over Cuba. Key Points: Ensemble perturbation simulations with RegCM4 show that land use change has contributed to the climate of the eastern United States and CubaFeedbacks from grid‐cell changes in land use alter low‐level regional circulation, which feeds back to the surface climateFrom 1650 to 1992, land use change in RegCM4 produced cooler and wetter conditions over the eastern United States, warmer and wetter conditions over Florida, and warmer and drier conditions over Cuba [ABSTRACT FROM AUTHOR]