The watershed of Darby Creek has an area of . A total of are in Chester County, are in Montgomery County, are in Delaware County, and are in Philadelphia. Darby Creek's watershed is often referred to as the "Darby-Cobbs watershed" since its largest tributary, Cobbs Creek, drains a total area of , or approximately one third of the Darby Creek watershed. The watershed is part of the Lower Delaware drainage basin. Neighboring major watersheds are Crum Creek to the west and the Schuylkill River to the east. The creek serves as the county line between Delaware County and Philadelphia County for a reach of . The creek's mouth is in the United States Geological Survey quadrangle of Bridgeport. However, its source is in the quadrangle of Valley Forge. The creek also passes through the quadrangles of Lansdowne and Norristown. There are 31 municipalities in the watershed, of which 26 are in Delaware County.