The Puyallup River and its main tributaries originate in the glaciers of Mount Rainier. These glaciers continually provide sediment such as silt and gravel to the rivers, creating sand and gravel bars. The thick sediment deposits in the stream beds lower water capacity, which causes the river to meander and flood during periods of high streamflow. It also causes the rivers to become braided and meandering. During the summer glacial meltwater dominates the streamflow, turning the Puyallup River turbid. In addition, the glaciers delay the onset of spring-summer runoff, compared to unglaciated river basins. Historically, these factors resulted in frequent flooding and extensive floodplain wetlands, and provided a rich and complex habitat for fish and other animals. In addition, the river's mouth at Commencement Bay occupied an extensive tidal flat and wetland estuary delta. Urbanization and an extensive system of flood control structures such as dams, levees, and culverts, have radically altered much of the Puyallup River and its tributaries. The estuary delta at the mouth of the Puyallup River has been almost completely replaced with the facilities of the Port of Tacoma, with less than 5% of the original estuarine habitat remaining. A fall run of chinook salmon occurs on the river. coho, chum, and pink salmon are also found in the river, along with steelhead, sea-run coastal cutthroat trout, and a threatened species, bull trout. Sockeye salmon are considered indigenous to the basin, but are rarely seen today. The river is named for the Puyallup tribe, who lived throughout the river basin. 

The Puyallup River begins in two forks, the North Puyallup River and the South Puyallup River. Both originate at glaciers on Mount Rainier. The North Puyallup River flows from the toe of Puyallup Glacier, while the South Puyallup River flows from Tahoma Glacier. The two streams flow through the western part of Mount Rainier National Park, joining just outside the park boundary and forming the Puyallup River proper. The main Puyallup River flows north and northwest from Mount Rainier. The tributary Mowich River, which also flows from glaciers on Mount Rainier, joins the Puyallup from the east. Below the Mowich confluence, the Puyallup River flows through a rugged region of mountains and foothills. The river is dammed at Electron Diversion Dam shortly below the Mowich confluence. The dam diverts a portion of the Puyallup River into a long flume, which runs for several miles to Electron, where the water is passed through turbines in a hydroelectric powerhouse before being returned to the river. The Puyallup River passes through a steep and narrow gorge between Electron Dam and the powerhouse. After Electron the river turns north and flows by the city of Orting, where it is joined by the Carbon River from the east. The Puyallup continues its northerly course after Orting. At Sumner, the river is joined by the White River. At the White River confluence, the Puyallup River turns northwest, flowing by the cities of Puyallup and Fife, and through the Puyallup Indian Reservation, before emptying into Commencement Bay at the Port of Tacoma