The village was the focus of missionary efforts, and then was the staging area for raids on English settlements in Pennsylvania during the French and Indian War.

Canasatego of the Six Nations, enforcing the Walking Purchase on behalf of George Thomas, Deputy Governor of Pennsylvania, ordered the Delaware Indians to go to two places on the Susquehanna River,[7]: 107–108  Wyomink and Shamokin.

[8]: 192  Early in the eighteenth century, the village consisted of Iroquois migrants from the north, as well as Shawnee and Lenape settlers moving away from expanding white settlements in Pennsylvania, and also some Saponi and Tutelo from Virginia.

[10] A 1727 map by John Taylor, of the forks of the Susquehanna River, shows Shamokin on both north and south banks of the west branch, with James Le Tort's store to the east.

[3]: 339  James Le Tort established a trading post at Chillisquaque Creek (known at the time by colonists as "Chenastry") about six miles north of Shamokin.

Anthony Sadowski wrote to John Petty in August, 1728 that "the Sauanos [Shawnees] have hanged Timothy Higgins upon a pole of their cabin," although he does not say why.

McKee holds a captain's commission under the government; is an extensive Indian Trader; bears a good name among them; and drives a brisk trade with the Allegheny country.

[3]: 210 In August 1736, Chief Allumapees (Sassoonan) visited Philadelphia and reported that "some of the Six Nations had been lately at Shamokin and had enquired kindly touching their Brethren there, towards whom they shewed much Love and Friendship.

"[13]: 54  On 18 September, The Pennsylvania Provincial Council was informed by Conrad Weiser that "there was a large number of those People with many of their Chiefs arrived at Shamokin, on Sasquehanna."

Count Nicolaus von Zinzendorf visited Shamokin together with Conrad Weiser and Anna Nitschmann in September, 1742, and met there with Shikellamy.

[2]: 84 After a series of violent conflicts between Indians and white settlers, Meshemethequater, Sassoonan and other chiefs from the Six Nations (including Shikellamy), the Tuscaroras, and the Lenape met with Conrad Weiser and Andrew Montour at Shamokin on 4 February 1743, and received wampum from Weiser, who was trying to persuade the Shawnees not to attack English traders living on the Allegheny, to prevent war from erupting.

It contains eight cabbins near the river's bank...It is by means of this neighborhood that we may reasonably hope...that a very beneficial trade may be extended...I quartered in a trader's cabbin, and about midnight the Indians came and called up him and his squaw...She sold the Indians rum, with which being quickly intoxicated, men and women began first to sing and then dance around the fire; then the women would run out to other cabbins and soon return, leaving the men singing and dancing the war dance, which continued all the next day...As soon as we alighted they shewed us where to lay our baggage, and then brought us a bowl of boiled squashes cold...I had learnt not to despise good Indian food.

Here we found a fine meadow of grass on our right, and rich dry ground on the left...peach-trees, plumbs, and excellent grapes.

The Indians of this place are accounted the most drunken, mischievous, and ruffian-like fellows of any in these parts; and Satan seems to have his seat in this town in an eminent manner.

[20]: 233–234  The Moravian mission in Shamokin was set up in 1747 primarily as a blacksmith’s shop to serve the Iroquois and their protected tribes, the Delaware, Tutelo, Conoy, and Shawnee.

In April of 1747, Shikellamy insisted to missionary John Martin Mack that any work done at the smith for the Five Nations should be without charge, saying, "I desire, T’girketonti (Spangenberg's Iroquois name) my brother, that when something is done to their flints that it is done for free, because they have nothing with which to pay.

[21] In the late spring of 1747, Moravian missionaries arrived in Shamokin and discussed the blacksmith project in a conference with the chief Shikellamy and his advisors.

He gave Schmidt an Iroquois name, Rachwistonis, and immediately accompanied him and Hagen down the river to Harris' Ferry to collect the rest of the tools for the blacksmith's shop.

"[8]: 215  According to Weslager, "the Pennsylvania authorities had no opposition to the Six Nations reserving Wyoming and Shamokin from the sale, since friendly Delawares, including Teedyuscung and his people living in those settlements--and any other Indians who might be placed there--constituted a buffer against Connecticut.

[8]: 229  On 16 October 1755 Lenape Indians allied with the French attacked and destroyed the town of Penns Creek, Pennsylvania about ten miles west of Shamokin.

Trading post owner John Harris Jr. wrote to the governor and offered to lead an expedition upriver to try to pacify the Native Americans and find out the mindset of those at Shamokin, since the Indians there were known to be friendly to settlers.

Andrew Montour, an Indian of mixed Oneida, Algonquin and French ancestry, was among those painted in black but was known to Harris and often acted as an interpreter.

On 25 October they were ambushed by twenty or thirty Lenape, who fired on them, forcing Harris's men to jump into the river, where four of them drowned while trying to reach the opposite bank.

[3]: 209  on 28 October Harris sent a report to the governor in which he states: The Indians are all assembling themselves at Shamokin to counsel; a large body of them were there four days ago.

Plans to build a fort on the Susquehanna were made in late 1755, but not implemented until June 1756 when Colonel William Clapham and Major James Burd finally received sufficient funding and supplies to begin construction at the site of the village of Shamokin.

[28] In November 1756, Colonel Clapham informed Deputy Governor William Denny that about fifty miles up the West Branch Susquehanna River was an Indian village with only ten families, located near Great Island (now known as Lock Haven, Pennsylvania).

He ordered a raiding party of 42 men, with Andrew Montour acting as a guide, to destroy the village,[29]: 573 [30]: 285  and instructed the commander, Captain Hambright, "to Kill, Scalp, and capture as many as you can."

Numerous Native American artifacts, dating mainly to the Archaic and Middle Woodland periods between nine thousand and fifteen hundred years ago, were recovered.

[6] Pennsylvania Historical and Museum Commission archaeologists also found gunflints, musket balls, broken glass, white clay pipe fragments, and a variety of metal objects, many of which can be dated to the mid-eighteenth century.

[6] Portions of a palisade wall, a trench, and a dry moat were discovered and artifacts such as burned cow, sheep, pig, and horse bones, gun parts, buttons, cannon balls, and glazed colonial ceramics as well as fragments of iron and brass, slag, charcoal, worked gun parts, stone from a foundation, and highly oxidized soil indicated the presence of a blacksmith shop.