The name of the river comes from a Pottawatomie word Sain-guee-mon (pronounced "sang gä mun") meaning "where there is plenty to eat." In the 18th century, groups of the Kickapoo settled along the river. In the middle 18th century, the region near the river was the scene of a conflict between the Illini and Fox as part of the larger French and Iroquois Wars. French traders were active in the region throughout the middle 18th century when it was part of the Illinois Country.

The first U.S. settlers arrived in the region in the 1810s. In 1821, Elijah Iles built a log-framed store, the first commercial building in Springfield. Groups of Cumberland Presbyterians settled the river valley beginning in 1825, giving the region a distinctive culture identified and described at the turn of the 20th century by Edgar Lee Masters.

Abraham Lincoln arrived with his family in the area in 1830 to settle a section of government land bisected by the river. The site, now Lincoln Trail Homestead State Memorial, was selected by Lincoln's father after the family had economic and land-title difficulties in Indiana. The 21-year-old Lincoln helped build a 16 foot by 16 foot (4.8 m by 4.8 m) cabin along the river. The following year in 1831, he canoed down the river to homestead on his own near New Salem in Menard County northwest of Springfield. Later that year he floated down the river with companions on a flatboat to the Illinois River, and then following the Mississippi River to New Orleans.

Lincoln was impressed by the navigational difficulties on the river, especially during the arrival of the first steamship, the Talisman, a 15-ton steamer," up the river to Springfield in March of 1832. Some sources state that Lincoln himself piloted the first steamship up the Sangamon to Springfield, accomplishing this feat with many men, almost as large as Lincoln, with axes to chop through whatever trees impeded the journey. More likely Lincoln acted as a guide and axeman. In later years, he told of taking a steamship three miles (5 km) into the prairie after losing his way on the Sangamon during a flood. During his first campaign for the Illinois General Assembly in 1832, he made navigational improvements on the river a centerpiece of his platform.