With the increasing exposure of populations and economy to natural hazards, the spatio-temporal characteristics of extreme rainfall remain a key subject of study. Based on annual maximum rainfall (AM) and peaks over threshold rainfall series at 30 meteorological stations during 1960–2011 in the Huai River Basin (HRB), spatio-temporal characteristics of extreme rainfall are analyzed through regional frequency analysis method using L-moments. The accuracy and uncertainty analysis of quantile estimations are also carried out, and the regional and at-site frequency analyses are compared. Results indicate the following: (1) During 1960–2011, AM precipitation at 20 stations in the HRB shows an increasing trend, while at the other 10 stations, it shows a decreasing trend. And both the increased and decreased trends are not significant. (2) The HRB can be categorized into three homogeneous regions via cluster analysis. For both at-site and regional frequency analyses, the root mean square error values increase with the increase in return periods. The estimations are reliable enough for the return periods of less than 100 years. The quantile estimates of large return period from regional frequency analysis are more accurate and have smaller uncertainty than those from at-site frequency analysis. (3) Extreme precipitation in the HRB concentrates in the upstream of the Huai River and YiShuSi water system in the east of the HRB. Generally, the area with extreme precipitation, especially the upper reaches of the Huai River and Yimeng Mountain areas, also has large standard variations of extreme precipitation, which will increase the risk of natural hazards.