The forests and grasslands in the U.S. are vulnerable to global warming and extreme weather events. Current satellites do not provide historical vegetation density images over the long term (more than 50 years), which has restricted the documentation of key ecological processes and their resultant responses over decades due to the absence of large-scale and long-term monitoring studies. We performed point-by-point regression and collected data from 391 tree-ring plots to reconstruct the annual normalized difference vegetation index (NDVI) time-series maps for the contiguous U.S. from 1850 to 2010. Among three machine learning approaches for regressions—Support Vector Machine (SVM), General Regression Neural Network (GRNN), and Random Forest (RF)—we chose GRNN regression to simulate the annual NDVI with lowest Root Mean Square Error (RMSE) and highest adjusted R2. From the Little Ice Age to the present, the NDVI increased by 6.73% across the contiguous U.S., except during some extreme events such as the Dust Bowl drought, during which the averaged NDVI decreased, particularly in New Mexico. The NDVI trend was positive in the Northern Forest, Tropical Humid Forest, Northern West Forest Mountains, Marin West Coast Forests, and Mediterranean California, while other ecoregions showed a negative trend. At the state level, Washington and Louisiana had significantly positive correlations with temperature (p < 0.05). Washington had a significantly negative correlation with precipitation (p < 0.05), whereas Oklahoma had a significantly positive correlation (p < 0.05) with precipitation. This study provides insights into the spatial distribution of paleo-vegetation and its climate drivers. This study is the first to attempt a national-scale reconstruction of the NDVI over such a long period (151 years) using tree rings and machine learning.