The frequency and intensity of droughts are increasing in many parts of the world as a result of global climate change and human activity, posing a serious threat to regional ecological security. The climate in the middle reaches of the Yellow River Basin (MRYRB) has been warm and dry in recent years, with frequent droughts. In order to investigate the temporal trend of drought, and reveal the resistance of vegetation to drought in the MRYRB, this study used remotely-sensed vegetation index products (MODIS-NDVI and SPOT-NDVI) and the standardized precipitation evapotranspiration index (SPEI). The results indicated that: (1) drought intensity showed a weak upward trend in the study area from 2000 to 2018, with linear growth rates of SPEI at temporal scales of 1, 3, 6, 9 and 12 months of −0.002, 0.0034, 0.0198, 0.0234, and 0.0249, respectively; (2) drought was positively correlated with vegetation in most areas (97.6%), and vegetation was most affected by drought on long-term time scales (9 and 12 months); (3) with the extension of drought, vegetation resistance index decreased, then gradually recovered after the end of the drought. Forest had the longest resistance duration of 260 days, while grassland and cultivated land had resistance durations of only 170 days. This study adds to the understanding of vegetation’s ability to withstand drought, and these findings provide evidence to support drought response in the MRYRB.