The Normalized Difference Vegetation Index (NDVI) derived from the Advanced Very High Resolution Radiometer (AVHRR) has been widely used to monitor moisture-related vegetation condition. The relationship between vegetation vigor and moisture availability, however, is complex and has not been adequately studied with satellite sensor data. To better understand this relationship, an analysis was conducted on time series of monthly NDVI (1989–2000) during the growing season in the north and central U.S. Great Plains. The NDVI was correlated to the Standardized Precipitation Index (SPI), a multiple-time scale meteorological-drought index based on precipitation. The 3-month SPI was found to have the best correlation with the NDVI, indicating lag and cumulative effects of precipitation on vegetation, but the correlation between NDVI and SPI varies significantly between months. The highest correlations occurred during the middle of the growing season, and lower correlations were noted at the beginning and end of the growing season in most of the area. A regression model with seasonal dummy variables reveals that the relationship between the NDVI and SPI is significant in both grasslands and croplands, if this seasonal effect is taken into account. Spatially, the best NDVI–SPI relationship occurred in areas with low soil water-holding capacity. Our most important finding is that NDVI is an effective indicator of vegetation-moisture condition, but seasonal timing should be taken into consideration when monitoring drought with the NDVI.