The valley surrounding the Big Sewickley Creek was surveyed in 1785 and sold to American Revolutionary War veterans. After the Battle of Fallen Timbers in 1794, settlers began to trickle in to the area, with flatboats, keelboats, and steamboats forming an industry along the Ohio River.

In 1911, the Sewickley Bridge was completed, bringing an end to the ferry industry. Ohio River Boulevard, later designated a part of Pennsylvania Route 65, was completed in 1934.

Historian Charles A. Hanna suggested "Sewickley&qyot; came from Creek words for "raccoon" (sawi) and "town" (ukli). According to Hanna, the Asswikale branch of the Shawnee probably borrowed their name from the neighboring Sawokli Muscogee before the former's migration from present-day South Carolina to Pennsylvania. Contemporary accounts from noted anthropologist Frederick Webb Hodge and the Sewickley Presbyterian Church, as well as the current Sewickley Valley Historical Society concur to varying degrees with Hanna's etymology. Some locals alternatively consider Sewickley to be a Native American word meaning "sweet water."

Sewickley has four land borders with Edgeworth to the northwest, Glen Osborne to the southwest, Sewickley Heights to the northeast, and Aleppo Township to the east. Across the Ohio River, Sewickley runs adjacent with Moon Township and Coraopolis with the Sewickley Bridge as the direct link to the former.

Along with the four land borders, plus Bell Acres, Glenfield, Haysville, Leetsdale, Leet Township, and Sewickley Hills, Sewickley is located in the Quaker Valley School District. Together, these boroughs and townships constitute a loosely defined region in northwestern Allegheny County. Most of these municipalities – not including Leetsdale and parts of Leet Township – share the Sewickley post office and its 15143 zip code.