The city received considerable media attention in 1997 when Carlisle residents Kenny and Bobbi McCaughey (pronounced "McCoy") became the parents of the world's first surviving set of septuplets.

Jeremiah "Uncle Jerry" Church was an early settler in Iowa, who arrived in Fort Des Moines in the summer of 1845.

[4] He laid out a new town in Polk County, just north of the border with Warren, in the winter of 1845 that he named Dudley.

[4] The tale goes that he staked his claim of Dudley at midnight on 1845-10-11 by the light of some burning Native American dwellings that he had set on fire.

[4][5] But the town did not last very long, as it was destroyed by the Flood of 1851, the commissioners having earlier noted in their rejection of it for county seat that it was located on low ground.

[4] So Church, who also founded Brooklyn, Iowa alongside T. K. Brooks and William Lamb (a town that he put forward as a contender for the state capital), set out on his third attempt at a town in Polk, which he named Carlisle and laid out in 1851 with David Moore.

[4][6][7] This was also located in Polk, 2 miles (3.2 km) south-west of the former Dudley, but the county borders were changed in 1852, which relocated it to the southern half of Allen Township, which was split in two in order to restore a so-called "stolen strip" in the north of Warren County.

[6][8] The town experienced growth in 1871 when the railroad was built through it, with the town's primary business area, until that time located at the top of a hill, moving down to the valley where the railway line was located, leaving the hill as a primarily residential area, with homes and churches.

B. Shoemaker, Daniel Moore, James Mount, Thomas Obriety, a Dr. Ward, Hugh Marshman, and Edwin Oaks.

[8] The actual mill, a 4 storey building housing two runs of burrs, was completed in June 1856, at a cost of US$10,500 (equivalent to $356,067 in 2023).

[10] Robert Nicholson bought it in 1863, and proceeded in 1874 to extend it lengthwise so that it could house five runs of burrs and two purifiers, driven by a 40 horsepower (30 kW) engine.

[10] Carlisle's first schoolhouse was built in 1853 and the building itself lasted through at least 1879, although by that time it had become merely a private home.

[4] By 1879 the town had a population of around 500, four churches (Methodist, Baptist, Christian, and United Bretheren), two general stores, three groceries, three drug stores, four physicians, a blacksmith, a wagon maker, a mechanic, a grain dealer, a hotel, a pottery, a brick yard, a meat market, a tin, hardware, & cabinet shop, and a shoe shop.

[12] According to the United States Census Bureau, the city has a total area of 5.56 square miles (14.40 km2), all land.