The South Platte River (Sioux: Wašíŋ-Wakpá [waˈʃĩ wakˈpa] lit. “bison tallow river”) is one of the two principal tributaries of the Platte River. Flowing through the U.S. states of Colorado and Nebraska, it is itself a major river of the American Midwest and the American Southwest/Mountain West. Its drainage basin includes much of the eastern flank of the Rocky Mountains in Colorado, much of the populated region known as the Colorado Front Range and Eastern Plains, and a portion of southeastern Wyoming in the vicinity of the city of Cheyenne. It joins the North Platte River in western Nebraska to form the Platte, which then flows across Nebraska to the Missouri. The river serves as the principal source of water for eastern Colorado. In its valley along the foothills in Colorado, it has permitted agriculture in an area of the Colorado Piedmont and Great Plains that is otherwise arid.

The river is formed in Park County, Colorado, southwest of Denver in the South Park grassland basin by the confluence of the South Fork and Middle Fork, about 15 mi (24 km) southeast of Fairplay. Both forks rise along the eastern flank of the Mosquito Range, on the western side of South Park, which is drained by the tributaries at the headwaters of the river. From South Park, it passes through 50 mi (80 km) of the Platte Canyon and its lower section, Waterton Canyon. Here, it is joined by the North Fork before emerging from the foothills southwest of the Denver suburb of Littleton. At Littleton, the river is impounded to form Chatfield Reservoir, a flood-control basin for the Denver metropolitan area.

The river flows north through central Denver, which was founded along its banks at its confluence with Cherry Creek. The valley through Denver is highly industrialized, serving generally as the route for both the railroad lines, as well as Interstate 25. On the north side of Denver, it is joined somewhat inconspicuously by Clear Creek, which descends from the mountains to the west in a canyon that was the cradle of the Pike's Peak Gold Rush. North of Denver, it flows through the agricultural heartland of the Piedmont (a shale region that was formed through erosion by the ancestor of the river following the creation of the Rockies). It flows directly past the communities of Brighton and Fort Lupton, and is joined in succession by Saint Vrain Creek, the Little Thompson River, the Big Thompson River, and the Cache la Poudre River, which it receives just east of Greeley.

East of Greeley, it turns eastward, flowing across the Colorado Eastern Plains, past Fort Morgan and Brush, where it turns northeastward. It continues past Sterling, and runs into Nebraska between Julesburg, Colorado, and Big Springs, Nebraska. In Nebraska, it passes south of Ogallala and joins the North Platte River near the city of North Platte.

The South Platte River through Denver is on the U.S. Environmental Protection Agency's (US EPA) list of impaired waterbodies for pathogen impairment, with E. coli as the representative pathogen species. Other water issues involve the appearance of the New Zealand mud snail and zebra mussel.

The flows of the South Platte have been greatly modified by human activity. Originally the river was seasonal north of Fort Morgan to its confluence with the North Platte. In the 1800s the river would disappear in July, August, and September due to low flows and a sandy river bottom. By 1910 the increase in agriculture caused the river to reach the border of Colorado and Nebraska due to return flows and dams holding back water later in the year. Increasing diversions from the upper Colorado River in the 20th century mean that flows reach the North Platte year round.

The South Platte was originally called Niinéniiniicíihéhe by the native Arapaho people who lived on its banks. The early Spanish explorers called it the Rio Chato (calm river). In 1702, it was named the Rio Jesus Maria by Captain Jose Naranjo, the Indigenous-Spanish scout and captain of war of the New Mexico Indian Auxiliaries, who was ordered by the viceroy of New Spain to search the Tierra Incognita for a French incursion into New Mexico. The South Platte also served as a vital water source in Colorado. Long before the city of Denver was created, many travelers came to the South Platte River to escape the arid Great Plains. These people could survive the heat, but not without the vital water source that the South Platte gave them. Buckets and wells sufficed as a water system for a while, but eventually, the Denver Water System was created.

In the late 1830s, four fur trading outposts were established on the river.