Guizhou is an important agriculture area locating in the southwest of China with maize and rice as its main food crops. Food security here is of great importance to maintain the stability of the minorities. However, droughts have frequently taken place recently, and resulted in big reductions in the crop yield. Under the circumstance of global climate change, therefore, the understanding of the temporal and spatial characteristics of drought and its relation with the climate mutation is of necessity for drought prevention and mitigation. We collected the daily meteorological data of 19 stations in Guizhou Province during 1960-2013. In consideration of the accumulated drought effect and the water requirement of autumn crops, the standard Precipitation-Evaporation index at six-month time scale between April and September (Sep-SPEI-6) was calculated. The correlation analysis between Sep-SPEI-6 and the crop yield reduction was tested. By use of multiple methods, i.e., Mann-Kendall, sliding t-test, Morlet wavelet cycle analysis and Hurst index, the spatial and temporal variation of drought were analyzed. Some results were obtained as bellow. Sep-SPEI-6 in Guizhou Province and the 9 cities showed a significant negative correlation with the annual crop yield reduction. The climate mutation occurred twice around year 1991 and year 2001. Compared with that in the first phase between 1960 and 1991, the occurring frequency and extent of droughts in the second stage between 1992 and 2001 decreased 10.59%. Compared with that in the second stage, the occurring frequency and extent of droughts increased 23.67% and 24.74% respectively in the third phase between 2002 and 2013. In contrast to the former two stages, the third one had significantly increased duration and intensity of drought. There was an obvious periodic oscillation in time series of Sep-SPEI-6, and 22 years was the first primary period. The Hurst index of Sep-SPEI-6 at different stations were all greater than 0.5, suggesting a better continuity in the Sep-SPEI-6 variation. The high drought frequency region tended to move to the west. The days of precipitation greater than 1 mm and the accumulative sunshine hours during the crop growth were both found the main factors affecting the meteorological drought in Guizhou Province. These results are fundamental to the decision of drought mitigation measures.