Santaquin was settled in spring 1851 by Benjamin F. Johnson and others, and initially known as Summit City, Summit Creek, or just Summit due to its location near the highest point between Utah and Juab Valleys. Though Johnson formed a friendship with an Indian chief named Guffich, the settlers were forced to flee to Payson in 1853 due to hostilities. In 1855, they returned and built a fort. In early 1856, Chief Guffich warned of an impending raid led by his son, Santaquin. The settlers fled, and when Santaquin and his men arrived Guffich informed him that the settlers were good people and had been warned by the Great Spirit. Peace was made, and Summit was to be renamed in Guffich's honor, but the chief insisted it instead be named for Santaquin.

Santaquin was not only a fertile farming community, but also an industrious one, boasting sawmills, a flour mill, a molasses mill, and a furniture shop. The town was reached by the Utah Southern Railroad in 1875, around which time valuable mineral deposits were located nearby. By the turn of the century, the population approached 900, a number which exceeded 1000 by 1930. On January 4, 1932, the City of Santaquin was incorporated.

Flooding in 1949 led to the construction of a reservoir by the Summit Creek Canal & Irrigation Company, preventing further damage to the community. A diversion dam and pipeline completed in 1971 expanded Santaquin's farmland, and farmers rapidly relocated here away from areas of rapid development to the north. Today, some 10,000 people live in Santaquin, and a few historic buildings remain in the heart of town.