The region is historically notable for its influence in helping fuel the American Industrial Revolution with its many anthracite coal mines.

The Susquehanna River occupies the southern part of the valley, which is notable for its deposits of anthracite.

The Pocono Mountains, a ridgeline away, are often visible from higher elevations to the east and to the southeast of the Wyoming Valley.

King Charles II of England granted the land to the Colony of Connecticut in 1662, and then to William Penn in 1681, who established the Province of Pennsylvania, leading to military skirmishes known as the Pennamite–Yankee War.

After Yankee settlers from Connecticut founded Wilkes-Barre in 1769, armed bands of Pennsylvanians,, known as Pennamites, tried unsuccessfully to expel them between 1769 and 70, and then again in 1775.

This led the Pennsylvania General Assembly to pass a resolution creating Luzerne County.

It was named after Chevalier de la Luzerne, a French soldier and diplomat during the 18th century.

Hazleton was added as a primary city in the 1990 census, while Monroe County lost its metropolitan status.

After the 2000 census, Columbia County lost metropolitan status, while Hazleton was removed as a primary city.

Scranton is the cultural center of the Wyoming Valley, being the largest city by population in the metropolitan area.

Local attractions include the Mohegan Sun Arena at Casey Plaza in Wilkes-Barre, the Pocono Raceway in Long Pond, PNC Field in Moosic, Mohegan Pennsylvania in Plains, the Toyota Pavilion in Scranton, the Wyoming Valley Mall in Wilkes-Barre, the Shoppes at Montage in Moosic, the Steamtown Mall in Scranton, the Viewmont Mall in Scranton/Dickson City, Pennsylvania, and the Montage Mountain Waterpark/Ski Resort in Scranton.

This area is celebrated in Lydia Sigourney's poem Vale of Wyoming published in her Scenes in my Native Land, 1845, with accompanying descriptive text.