Based on the records of drought and flood in Chinese historical documents and precipitation data during the instrumental period, and by using the five-grade classification method, this study reconstructs the drought and flood grades in the Hanjiang River Basin from 1426–2017 and analyzes their spatial and temporal variation characteristics. The results show that, on the centennial scale, drought and flood variation in the basin exhibited two dry periods (early fifteenth century to early sixteenth century, early twentieth century to the present) and one four-century long wet period (early sixteenth to early twentieth centuries), with multi-decadal drought and flood fluctuations within each period. Meanwhile, the variation shows some regional differences. For example, droughts and floods both occurred at high rates in the whole river basin during the twentieth century, with the increase in droughts relatively more remarkable in the upper reaches and the increase in floods more notable in the middle and lower reaches; throughout the study period, the drought and flood variability was larger in the upper reaches, but the drought and flood frequency was higher in the middle and lower reaches. In addition, there are a few quasi-cycles of the drought and flood variability in the middle and lower reaches, which include the quasi-cycles of 2–8 years, 10–30 years, 50 years, and 80–100 years, respectively. The upper reaches are slightly different, which have the quasi-cycles of 3–5 years, 10–30 years, and 70–80 years, respectively.