Littleton was the site of the sixth Praying Indian village established by John Eliot in 1645 consisting of mainly Native Americans of the Massachusett tribes.

[2]At the time of King Philip's War between the English and Native Americans, the General Court ordered the Indians at Nashoba to be interned in Concord.

Around this time, fourteen armed men of Chelmsford went to the outlying camp at Wameset (near Forge Pond) and opened fire on the unsuspecting Nashoba, wounding five women and children, and killing outright a boy twelve years old, the only son of John Tahattawan.

When increasing numbers of Massachusetts Bay officers began successfully using Praying Indians as scouts in the war, the sentiment of the white settlers turned.

Residents of Littleton contributed men to the militia system that was set up by the Crown to serve as self-defense against hostile First Nations peoples as well as the French in Canada.

The militia company and the minutemen squads mustered at Liberty Square located on the southwest side of town on the Boxborough line (then part of Littleton).

Besides bringing about a brief return to public debating, the War was also long a subject for Lyceum, a venue where veterans lectured about their experiences and travel.

The Stony Brook Railroad line running from present day Ayer to Chelmsford maintained a station in North Littleton by Forge Pond.

In 1885, the quarantine station for the Port of Boston moved from Waltham to a farm on the Fitchburg railway line on the south west side of Mill Pond.

The elder Houghton, a Littleton native, had in 1884 made a bequest to the town for the establishment of a library collection in honor of Reuben Hoar, who had financially assisted his father in a difficult time.

Herbert Whitcomb also ran a commercial dairy, which he sold in 1942 to J. Fred Herpy, a dairyman who had moved to Littleton from Rome, New York.

On the site of the Great Road plant, Herpy built two large swimming pools, and added a bathhouse, grill and ice cream stand.

Like many towns along the state roads radiating from Boston, the advent of motor transport saw the arrival of truck farms which sprang up along Route 119/2A.

While earlier commercial market gardens had sprung up along the railways, motor transport allowed the formation of produce wholesalers in outlying cities such as Fitchburg and Lowell which signed contracts with local farmers to provide goods on a daily basis for sale in Haymarket.

While in Somerville, Arthur Rowse, known for integrity and honesty, had refused to do business with bootleggers in a state where Prohibition was overwhelmingly unpopular.

Only in the late 1980s, with the building of DEC's King Street facility, was a bar allowed to open in town (this later became Ken's American Cafe, which closed in December 2008.

For years, residents could go to establishments just over the town line that served alcohol, in the surrounding Acton, Westford, Groton, Ayer, and Boxborough.

In the post-World War II era, Roman Catholic immigrants from Ireland, Quebec, Canada, and Italy moved into Middlesex County and Littleton.

Many of the early families are represented by descendants in the town to the present day: Blanchard, Bulkeley, Crane, Hartwell, Hathaway, Kimball, and Whitcomb.

Many ethnic Irish, Italian, Québécois, and Finnish families moved here in the 1950s and 1960s in a kind of suburbanization after leaving their more dense, first and second-generation neighborhoods in Arlington, East Boston, Cambridge, Lowell, and Somerville.

Author John Hanson Mitchell wrote a book titled Ceremonial Time (1984), which details a history of fifteen thousand years over one square mile located within the town.

The arrival of Digital Equipment Corporation (DEC, later part of Hewlett-Packard) in the 1970s connected the town to other businesses in the Boston-area high-tech corridor.

In 2022, the Boston Globe reported that the Littleton mill had the highest concentration of federally-licensed firearms dealers in the United States.

The library, still named in honor of Reuben Hoar, moved to 41 Shattuck Street in 1991, and the Houghton Memorial Building then housed the Littleton Historical Society.

Local Fraternal organizations that serve the town of Littleton are the Tahattawan Masonic Lodge, the Bishop Ruocco Council 9275 Knights of Columbus, the Acton Lions Club, and the Chelmsford and Maynard Elks.

Following the horrific demise of the Praying Indian village of Nashoba, Anglo settlers and immigrants bought land from the surviving members of the Nashoba congregation and built their meetinghouse in 1715 on the site of what is now the First Church Unitarian, at 19 Foster St.[26] The First Baptist Church Littleton, at 461 King St, was the second congregation in Littleton built in spring of 1822 because "Prayer meetings on weekdays, itinerant preaching, and all efforts for the conversion of the heathen, were stigmatized as the doings of fanatics."

The next creed to establish itself in Littleton was Roman Catholicism driven by the influx of Irish, Italian, Quebecois, Polish, Norwegian, and Portuguese immigrants.

With evangelization and this influx, the local Mormon community built the Littleton Ward of The Church of Jesus Christ of Latter-day Saints at 616 Reat Road in the 1980s.

The town has an ecummenical group, The Greater Littleton Interfaith Council that cooperates on various charity, faith, and relief activities.

The line currently serves as a major corridor of Pan Am Railway's District 3 which connects New Hampshire and Maine with western Massachusetts, Vermont, and New York.