In 1763, the Battle of Muncy Hills took place during the French and Indian War. It was a clash between the Native Americans and colonists seeking homestead sites in Native American territory. In 1768, at the Treaty of Fort Stanwix, the British purchased
the land that became Lycoming County from the Iroquois Nation who controlled the lands.

In March 1796 the first house was built in Williamsport. James Russell built his inn on what is now the northeastern corner of East Third and Mulberry Streets in downtown. On April 13, 1795 Lycoming County was formed from Northumberland County. It encompassed
all the lands of Northumberland County situated west of Muncy Hills and was a domain of 12,500 square miles (32,000 km^{<2/sup>), comprising most of north central Pennsylvania. In 1796 the first recorded childbirth in Williamsport was James Russell, the son
of Mr. and Mrs. William Russell and grandson of James Russell of the Russell Inn, and the first school was built as a one-room log addition to the building that would eventually become the first Lycoming County Courthouse. In 1798 the first brick house in Williamsport
was erected on Front Street, between Market and Mulberry, by Andrew Tulloh, a lawyer. The bricks were made on the banks of Grafius Run where that stream crossed Hepburn Street.}

In 1799, a post office opened at the corner of Third and State Streets in what is now downtown, and the following year, a jail was constructed at the northeast corner of William and Third Streets. The post office was later converted to a saloon.

In 1801, the town's first store was opened by William Winter on Third Street. In 1831 Jacob L. Mussina established the Repasz Band, the oldest brass band in America still in existence. On Oct. 15 1834 The West Branch Canal opened and the first boat to pass through
the canal en route to Jersey Shore was that of George Aughenbaugh. The first freight carried into town was iron for the foundry of John B. Hall. The same year the enactment of the common school law by Pennsylvania Legislature led to public education here. In May 1835,
the first public schools opened in Williamsport and also the town's first bank, the West Branch National Bank.

The Underground Railroad, used by enslaved African-Americans to obtain their freedom in the 30 years before the Civil War (1860–1865) included routes from states in the South, which supported slavery, to "free" states in the North and Canada. From 1830 until
1865, the underground railroad, a system of safe houses and routes for slaves escaping to freedom, operated in Lycoming County; many local abolitionists, including Daniel Hughes, served as conductors and agents.

Based on the oral history of Mamie Sweeting Diggs (1933–2011), fourth generation descent and great-granddaughter, Hughes, was a river raftsman on the Susquehanna river who had migrated from Oswego, New York. He lived on the Muncy Indian Reservation until he acquired
land off Freedom Road. During his trips transporting logs to Maryland, he brought escaped slaves back on foot from Baltimore, over Bald Eagle Mountain and hid them at his home and in the caves on Freedom Road.

Mamie's grandfather, Robert, helped his father, Daniel Hughes, hide escaped slaves in the caves behind their home on Freedom Road. They fed them, nursed the sick back to health and delivered them safely to the next "station", The Apker House in Trout Run.
The Apker House was the home of Robert Fairies, abolitionist and president of the Williamsport-Elmira Railroad. The railroad ran through his property where escaped slaves were hidden in the barn and house and then loaded into railway baggage cars for the trip to Elmira, NY,
the next "station."

Mamie's grandfather, Robert passed the stories to his children, including Mamie's mother, Marion. Marion tended the family homestead, maintained Freedom Road Cemetery (where nine black Civil War vets are buried) and passed Daniel's stories down to her children.

In 1849, the Market Street Bridge was built over the West Branch Susquehanna River. It was opened as a toll bridge to cover the state's costs of $23,797. In 1854, a brewery opened. The brewery was sold to Henry Flock in 1865. This brewery was run by the Flock family
until the 1940s. The Flocks' business survived Prohibition by converting to a dairy.

In 1875, the first tower clock in the United States to sound the Cambridge Quarters (Westminster Chime) was installed at Trinity Episcopal Church, a gift of Peter Herdic with bells given by judge J. W. Maynard. The following year, the Williamsport Hospital opened its first
facility April 1 at Elmira and Edwin Streets.

In 1881, a state law ended racial segregation in Pennsylvania schools. By 1948, all schools in this area were integrated. In 1895, Harry Houdini appeared in one of his earliest performances, at the Old Fair Grounds with The Welch Brothers Circus.

Williamsport was the birthplace of the national newspaper Grit in 1882. Williamsport purportedly once had more millionaires per-capita than anywhere else in the world. For this reason, the area's local high school, the Williamsport Area High School,
uses "Millionaires" as its team mascot.

The Flood of March 17–18, 1936 caused the river to crest at 33.9'. Flood waters reached High Street. It was known locally as the Hello, Al flood because Al Glaes, operating a short-wave radio station from his home on High Street, kept the city in touch with the rest
of the world after the flood disrupted electricity and telephone service.

On June 6, 1939 the first Little League Baseball game was played on a sandlot outside Bowman Field in Williamsport. Carl Stotz conceived the idea of a Little League, and he and Bert and George Bebble managed the first three teams. In 1941 the U.S. entered World War II
after the Japanese attacked Pearl Harbor. Williamsport native Joe Lockard, stationed on Oahu, gave warning of the impending attack based on radar readings. His readings were dismissed as American B17 bombers coming in from the mainland. Also in 1941 the Williamsport School
Board created the Williamsport Technical Institute for high school and post-high school students. It grew into the Williamsport Area Community College, and later became Pennsylvania College of Technology.

As of the 2020 census, it had a population of 27,754.