Pennsylvania may be divided into more than a dozen distinct physiographic regions, most of which extend in curved bands from east to south. Beginning in the southeast, the first region (including Philadelphia) is a narrow belt of coastal plain along the lower Delaware River; this area, at sea level, is the state's lowest region. The next belt, dominating the southeastern corner, is the Piedmont Plateau, a wide area of rolling hills and lowlands. The Great Valley, approximately 10–15 mi (16–24 km) in width, runs from the middle of the state's eastern border to the middle of its southern border. The eastern, central, and western parts of the Great Valley are known as the Lehigh, Lebanon, and Cumberland valleys, respectively. West and north of the Great Valley, the Pocono Plateau rises to about 2,200 ft (700 m). Next, in a band 50–60 mi (80–100 km) wide, most of the way from the north-central part of the eastern border to the west-central part of the southern border are the Appalachian Mountains, a distinctive region of parallel ridges and valleys.

The Allegheny High Plateau, part of the Appalachian Plateaus, makes up the western and northern parts of the state. The Allegheny Front, the escarpment along the eastern edge of the plateau, is the most striking topographical feature in Pennsylvania, dissected by many winding streams to form narrow, steep-sided valleys; the southwestern extension of the Allegheny High Plateau contains the state's highest peak, Mt. Davis, at 3,213 ft (980 m). A narrow lowland region, the Erie Plain, borders Lake Erie in the extreme northwestern part of the state.

According to federal sources, Pennsylvania has jurisdiction over 735 sq mi (1,904 sq km) of Lake Erie; the state government gives a figure of 891 sq mi (2,308 sq km). Pennsylvania contains about 250 natural lakes larger than 20 acres (8 ha), most of them in the glaciated regions of the northeast and northwest. The largest natural lake within the state's borders is Conneaut Lake, about 30 mi (48 km) south of the city of Erie, with an area of less than 1.5 sq mi (39 sq km); the largest manmade lake is Lake Wallenpaupack, in the Poconos, occupying about 9 sq mi (23 sq km). Pennsylvania claims more than 21 sq mi (54 sq km) of the Pymatuning Reservoir on the Ohio border.

The Susquehanna River and its tributaries drain more than 46% of the area of Pennsylvania, much of it in the Appalachian Mountains. The Delaware River forms Pennsylvania's eastern border and, like the Susquehanna, flows southeastward to the Atlantic Ocean. Most of the western part of the state is drained by the Allegheny and Monongahela rivers, which join at Pittsburgh to form the Ohio. The Beaver, Clarion, and Youghiogheny rivers are also important parts of this system.

During early geological history, the topography of Pennsylvania had the reverse of its present configurations, with mountains in the southeast and a large inland sea covering the rest of the state. This sea, which alternately expanded and contracted, interwove layers of vegetation (which later became coal) with layers of sandstone and shale.