The name is literal. Native Americans gathered salt from springs near the river long before French visitors did, and mapmakers labeled it the Saline. Surveyors working in 1819 followed the old Sauk Trail through the area, the route that became the Detroit-to-Chicago road and later US-12. Orange Risdon, who surveyed that road, bought land here in 1825 and helped plat the town on high ground north of the springs in 1832. It became a village in 1866 and a city in 1931.

Farming and the railroad built the place. The line from Ypsilanti to Hillsdale opened on July 4, 1870, and within a few years Saline was a leading farm shipping point for the region, with flour mills, tanneries and a windmill factory. The depot survives as a museum, and the Rentschler Farm Museum preserves a farmstead worked by one family from 1901 to 1998.

Downtown lines Michigan Avenue through the center of the city. Past it, the farm museum sits between the Sauk Trail Shopping Center and a large auto interiors plant that Ford moved here from Brooklyn, Michigan, in 1966. After stretches under Visteon and a Ford-run holding company, Faurecia took it over in 2012. Commercial property runs to historic storefronts, Michigan Avenue retail and industrial buildings.