Wetlands have powerful runoff regulation functions, which can effectively store and retain surface runoff. The runoff regulation function of wetlands is affected by wetland areas, which affect the capacity of flood control. To explore the law of the area change of the main wetlands of the Naolihe River Basin (MWNRB), the visual interpretation method was used to extract wetlands. To identify the reasons for area changes in the MWNRB, the maximum likelihood method, minimum distance method, and neural network method were used to classify land use types from remote sensing images; the M-K variation point test and Theil-Sen trend analysis were used to test the variation point and calculate the trend of precipitation and temperature series. To clarify the influence of wetland areas on runoff, the Gini coefficient and SRI of runoff were used to calculate runoff temporal inhomogeneity. The results showed that the area of the MWNRB obviously decreased, with 74.5 × 106 m2/year from 1993 to 2008, and increased slowly from 2008 to 2015, with 27.7 × 106 m2/year. From 1993 to 2008, 50.74% and 38.87% of wetlands were transformed into paddy fields and dry fields, respectively. From 2008 to 2015, 61.69% and 7.76% of wetlands were transformed from paddy fields and dry fields, respectively. The temperature of the MWNRB increased slowly by 0.04 °C/year from 1993 to 2008 and increased obviously by 0.16 °C/year from 2008 to 2015. The precipitation decreased by 5.6–8.1 mm/year and increased by 16.6–41.2 mm/year in 1993–2008 and 2008–2015, respectively. Compared with precipitation and temperature, land use change caused by human activities is the main cause of wetland area change. The area change of the MWNRB has a certain influence on the runoff regulation and storage capacity. The Gini coefficient and SRI index increased from 0.002/year (0.008) to 0.023/year from 1993 to 2008 and decreased from 0.046/year (0.045) to 0.161/year from 2008 to 2015, respectively.