Sanford is in the western portion of a tract of land purchased in 1661 from Abenaki Chief Fluellin by Major William Phillips, an owner of mills in Saco.

Following the Civil War, Sanford developed into a textile manufacturing center, connected to markets by the Portland and Rochester Railroad.

From 1880 to 1910, the mill town's population swelled from 2,700 to over 9,000, some living in houses built by the company and sold to workers at cost.

After moving the looms to its Southern plants, Burlington closed Sanford Mills—leaving 3,600 unemployed and 2,000,000 square feet (190,000 m2) of empty mills.

Local business owners began traveling the northeast, enticing employers to move to the area.

In November 1955, NBC's Armstrong Circle Theatre dramatized Sanford's comeback on television in “The Town that Refused to Die”,[10] starring Darren McGavin and Jason Robards.

[12] When the federal government offered money in the 1960s for urban renewal to rehabilitate aging or blighted districts, more than thirty Sanford structures were razed.

[9] Sanford was the home of Belle Ashton Leavitt, the third woman attorney admitted to the Maine Bar Association.

[14] The town gained national notoriety in 1984, when Scott Waterhouse, then age 18, strangled 12-year-old Gycelle Cote.

Rumors of Satanism surrounded the case, and some of Waterhouse's personal belongings were deemed to be occult in nature.

The furor culminated in several tabloid stories, national television coverage, and at least one headline referring to the town as "Terrortown!".

[citation needed] The town again gained national notoriety on November 9, 2009, when the Amber Alert system was first used in the state for 2-year-old Hailey Traynham, abducted by her father.

[16] In 2003, Maine voters rejected a proposal to build a $650 million casino in South Sanford.

The 362-acre (1.46 km2) development, ostensibly owned by the Penobscot and Passamaquoddy nations, would have included 4,000 slot machines, 180 gaming tables, a hotel, a 60,000-square-foot (5,600 m2) convention center and an 18-hole golf course.

Detractors predicted higher crime, traffic and an erosion of Maine's quality of life.

The flaming five-story back building of the former Stenton Trust Mill complex at 13 River Street brought more than 100 firefighters from 20 communities to battle the blaze.

[18] The 294,000-square-foot (27,300 m2) complex, which was built in 1922 as a textile mill, includes two five-story brick and concrete buildings and a one-story connecting structure.

The lowest elevation, which is approximately 140 feet (42.7 m) above sea level, is on the Mousam River at Old Falls Pond as it flows into Kennebunk.

Sanford borders the towns of Shapleigh, Acton, Alfred, Kennebunk, Wells, North Berwick, and Lebanon.

[citation needed] In 2018, Hutter Construction Co. workers built a new high school on a 127-acre campus in the center of town.

It is a career-focused school,[34] separated into four wings,[35] in which students select specialized courses geared towards their preferred future career.