The watershed of Buffalo Creek has an area of . The watershed contains the central portion of Union County and the eastern portion of Centre County. A total of 60 percent of the creek's watershed is forest. Much of this land is located in Bald Eagle State Forest. In general, most of the forested land in the watershed is in its northern and western areas. A total of 34 percent of the watershed is devoted to agriculture. Most of this land is situated near Lewisburg and Mifflinburg. The remaining 6 percent of the watershed's land is residential, urban, and industrial. The creek's watershed takes up the largest portion of Union County for any watershed. The drainage pattern of the watershed is dendritic.