Differencing multi-temporal topographic data (radar, lidar, or photogrammetrically derived point clouds or digital elevation models—DEMs) measures landscape change, with broad applications for scientific research, hazard management, industry, and urban planning. The United States Geological Survey’s 3D Elevation Program (3DEP) is an ambitious effort to collect light detection and ranging (lidar) topography over the United States’ lower 48 and Interferometric Synthetic Aperture Radar (IfSAR) in Alaska by 2023. The datasets collected through this program present an important opportunity to characterize topography and topographic change at regional and national scales. We present Indiana statewide topographic differencing results produced from the 2011–2013 and 2016–2020 lidar collections. We discuss the insights, challenges, and lessons learned from conducting large-scale differencing. Challenges include: (1) designing and implementing an automated differencing workflow over 94,000 km2 of high-resolution topography data, (2) ensuring sufficient computing resources, and (3) managing the analysis and visualization of the multiple terabytes of data. We highlight observations including infrastructure development, vegetation growth, and landscape change driven by agricultural practices, fluvial processes, and natural resource extraction. With 3DEP and the U.S. Interagency Elevation Inventory data, at least 37% of the Contiguous 48 U.S. states are already covered by repeat, openly available, high-resolution topography datasets, making topographic differencing possible.