Health varies by U.S. region of residence. Despite regional heterogeneity in the outbreak of COVID-19, regional differences in physical distancing behaviors over time are relatively unknown. This study examines regional variation in physical distancing trends during the COVID-19 pandemic and investigates variation by race and socioeconomic status (SES) within regions. Data from the 2015-2019 five-year American Community Survey were matched with anonymized location pings data from over 20 million mobile devices (SafeGraph, Inc.) at the Census block group level. We visually present trends in the stay-at-home proportion by Census region, race, and SES throughout 2020 and conduct regression analyses to examine these patterns. From March to December, the stay-at-home proportion was highest in the Northeast (0.25 in March to 0.35 in December) and lowest in the South (0.24 to 0.30). Across all regions, the stay-at-home proportion was higher in block groups with a higher percentage of Blacks, as Blacks disproportionately live in urban areas where stay-at-home rates were higher (0.009 [CI: 0.008, 0.009]). In the South, West, and Midwest, higher-SES block groups stayed home at the lowest rates pre-pandemic; however, this trend reversed throughout March before converging in the months following. In the Northeast, lower-SES block groups stayed home at comparable rates to higher-SES block groups during the height of the pandemic but diverged in the months following. Differences in physical distancing behaviors exist across U.S. regions, with a pronounced Southern and rural disadvantage. Results can be used to guide reopening and COVID-19 mitigation plans.