The Huai River Basin (HRB) is an important grain and industrial production area in eastern China with frequent droughts. Under the background of current climate change, the hydrological and meteorological characteristics of the basin may be changed, which may lead to the changes of regional drought characteristics. It should be paid more attention on the drought research under climate change and the difference between different drought indices. Coupled Model Intercomparison Project phase 5 (CMIP5) as an important tool for climate change research has been used in the study and the study chosen three global circulation models (GCMs)—such as CNRM-CM5 (CNR), HadGEM2-ES (Had), and MIROC5 (MIR)—to gather an ensemble model (EnM) for providing the future climate information. The Standardized Precipitation Index (SPI) and Humidity Index (HI) were used to evaluate and compare the drought situations in the past and the future periods with two representative concentration path scenarios (RCP4.5 & RCP8.5). Some sequence statistics methods, such as Mann–Kendall test and run theory, were carried out to analyze the trend and the changes of extreme drought frequency and characteristics values. The research showed that the simulation accuracy of the EnM would better. SPI and HI take different factors into count and thus lead to differences in describing drought trend, extreme drought frequency, and characteristic values, such as drought severity, drought duration, mean drought severity, and max drought intensity. The research showed that both SPI and HI showed the same wetting or drying trend in the same timescales (except winter) as in the historical data. However, the future annual and seasonal drought trend reflected by SPI shows a wetting trend while HI shows a drying trend. Both in the past and the future, extreme drought frequency and characteristic values reflected by HI are higher than SPI. The drought trend is greater, and the extreme drought frequency and characteristics tend to be strengthened under RCP8.5. Low precipitation and high potential evapotranspiration (PET), especially the PET caused by temperature rise, are the main influencing factors of drought in the future. Therefore, the influence of the PET should not be ignored in drought analysis and we should strengthen the comparative study of different drought indices in future drought analysis under climate change.