Climate and land-use changes are two major factors that significantly affect the watershed hydrology cycle. It is essential for regional water resource management to quantitatively assess the respective hydrological impact of these two factors. In this study, the Soil and Water Assessment Tool (SWAT) was constructed to quantify the contributions of climate and land-use changes to runoff at the annual and seasonal time scales in the Qinhuai River basin (QRB), where significant urbanization occurred from 1986 to 2015. Moreover, based on the partial least squares regression, the specific impact of individual land-use change on major hydrological components was evaluated at the sub-basin scale. The results showed that: (1) the predominant patterns of land-use change in the QRB included the transformations from paddy fields to urban areas and dry lands, forest to dry lands and dry lands to urban areas; (2) the flood seasonal precipitation series and all air temperature series had significant increasing trends over 1986–2015, and annual and seasonal runoff series had significant increasing trends and had an abrupt change point in 2001; (3) the average annual, flood seasonal, and non-flood seasonal runoff increased 238.5, 130.2 and 108.3 mm, of which land-use change was responsible for 77.6, 55.1, and 104.8% of the increases, respectively, while climate change was responsible for 22.4, 44.9, and −4.8%, respectively and (4) the hydrological response to land-use change showed an obvious decrease in actual evapotranspiration (ET) and significant increases in surface runoff and baseflow. The decrease of ET and increase of baseflow could be attributed to the conversion patterns from paddy fields and forest to dry lands, while the conversions from paddy fields and dry lands to urban areas caused a remarkable increase in surface runoff in the QRB. The study demonstrated that these practicable approaches were beneficial for the more unbiased views of the hydrological responses to climate change and land-use changes in the highly urbanized basin, which were also critical for the sustainable development of regional water resource and future land-use planning.