[1][2] The route crosses into Spruce Creek Township and heads into forested areas, curving northwest to run parallel to Norfolk Southern's Pittsburgh Line and the Little Juniata River which are both located northeast of the road.

[1][2] The route turns east and crosses the Little Juniata River, at which point it passes homes and some businesses in the community of Spruce Creek.

PA 45 curves northeast and heads through a mix of farmland and woodland with some homes parallel to the creek, with Rothrock State Forest and Tussey Mountain located a short distance to the southeast.

Past this intersection, the route heads northeast through an agricultural valley between The Barrens to the northwest and Tussey Mountain to the southeast.

[1][2] PA 45 enters Ferguson Township at Baileyville in Centre County and becomes West Pine Grove Road, heading east-northeast through farmland with some development in the Nittany Valley.

[1][3] At this point, PA 45 turns east for a concurrency with US 322 Bus., and the two routes head east-southeast on four-lane divided Boal Avenue.

The road passes south of the Pennsylvania Military Museum before it heads past homes and businesses in the community of Boalsburg.

Past this interchange, the road becomes undivided again and heads east-northeast through a mix of farmland and housing developments, passing to the north of a golf course.

Farther northeast, the road gains a center left-turn lane and passes homes and businesses before coming to an intersection with PA 144 in the community of Old Fort.

[1][3] From here, PA 45 narrows to two lanes and becomes Penns Valley Pike, continuing east-northeast through farmland with some residential and commercial development.

In the commercial downtown of Millheim, the route comes to an intersection with the southern terminus of PA 445 and becomes East Main Street.

The road leaves Millheim for Haines Township and turns to the east, passing through the residential community of Aaronsburg as Aaron's Square.

[1][3] The route leaves Aaronsburg and becomes Penns Valley Road, heading east through agricultural areas with some woods and homes and passing through the community of Fiedler.

[1][3] PA 45 enters Hartley Township in Union County and curves southeast as Old Turnpike Road, continuing through the Bald Eagle State Forest.

The road winds southeast before it turns east and leaves the state forest, coming to an intersection with the northern terminus of PA 235.

Here, the route becomes Chestnut Street and passes commercial development, coming to a junction with the northern terminus of PA 104.

Upon crossing US 15, PA 45 enters the borough of Lewisburg and heads northeast past homes along Market Street.

The road crosses a Union County Industrial Railroad line and continues into the commercial downtown of Lewisburg.

The route passes through the downtown before it runs through residential areas and comes to a bridge over the West Branch Susquehanna River.

The road heads away from the creek and crosses into Liberty Township in Montour County, running through agricultural areas with some trees and residences.

Narrow streets within the borough are avoided by this designation, and a complicated intersection with Pennsylvania Route 304, which does not contain turning lanes, is bypassed.

At mile 2.4, just south of Spruce Creek, a very old overpass, constructed from blocks of stone, carries Norfolk Southern's Pittsburgh Line over PA 45.