Great Seneca Creek is the largest watershed located entirely within Montgomery County. In addition, two large tributary systems flow into Great Seneca. These are Little Seneca Creek, and Dry Seneca. Almost every species of fish found in Montgomery County can be found in this watershed. Smallmouth bass have been found in the lower sections. Redbreast sunfish and central stonerollers are found throughout the middle section, and portions of the upper reaches support a cold water fish community. The Great Seneca headwaters begin near Hawkins Creamery Road southeast of Damascus and flow through low density residential and agriculture areas. Magruder Branch, a large tributary which begins in south Damascus, flows through county parkland and joins Great Seneca down river of Woodfield Rd. It then passes through commercial areas in Damascus and continues through low to medium density residential areas. Magruder Branch contains a system of vernal pools, built as mitigation for an adjoining hiker-biker trail system, that supports a diverse amphibian community. The Damascus Wastewater Treatment Plant (WWTP) is located in the Magruder Branch subwatershed.

Great Seneca Creek continues southwest of Laytonsville, rapidly increasing in size as other tributaries join it. Wildcat Branch, a naturally reproducing brown trout stream, and Goshen Branch join Great Seneca above Brink Road. Great Seneca Creek then flows through the Montgomery Village area, where land use densities increase considerably. Many of these areas were built before modern stormwater runoff controls were required by the State and, consequently, the quality of the stream channel has declined.

Below Route 355, Great Seneca picks up additional drainage from high density areas in Gaithersburg and Germantown. It then transitions back to low density residential with areas of agricultural land uses from approximately Riffle Ford Road in south Germantown down to the Potomac River. Along Clopper Mill Road one can see the ruins of a mill, and old photographs at the Seneca Creek State Park record a visual history of Great Seneca in this vicinity. The quality of the stream channel has significantly degraded, with areas of active stream bank erosion and long reaches of deep runs with fewer riffle areas than observed 20 years ago. Above Riffle Ford Road is the Seneca WWTP. Ongoing studies will provide a baseline record of stream conditions before plant expansion is scheduled to come online. Some concerns have been raised about the increased nutrient load into Great Seneca resulting from this and the Magruder WWTP.

Major tributaries in this portion of Great Seneca include Whetstone Run, Gunners Branch, and Long Draught Branch. These three tributaries all originate in high density residential areas and each have instream impoundments: Lake Whetstone, Gunners Lake, and Clopper Lake. Whetstone Run is occasionally blue-tinted from light-filtering dyes intended to reduce algae and aquatic plant growth in the lake.

Below Riffle Ford Road, some tributary areas of Great Seneca are changing from agriculture to low and medium density residential. Great Seneca flows westward towards Dawsonville. It is joined by Little Seneca Creek, becoming Seneca Creek below the confluence. Flowing south towards the Potomac River, Seneca Creek is joined by Dry Seneca Creek before flowing into the Potomac River above the Seneca Breaks. Many people enjoy fishing, sailing, and paddling within the mouth of the creek, and out on the Potomac River.

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