The section of road south of Center City Allentown was originally designated as part of US 309 when the U.S. Highway System was established in 1926.

The road becomes undivided at the Vera Cruz Road/Oakhurst Drive intersection and ascends South Mountain with S-curves, passing through forested areas with some homes.

The route reaches the community of Summit Lawn at the peak of South Mountain, where it intersects Rock Road, which heads southwest to provide access to westbound I-78/northbound PA 309.

The road crosses Emaus Avenue and narrows to two lanes, running north-northwest past businesses as it heads into the Mountainville neighborhood.

PA 145 continues past homes and businesses, curving to the north as it passes to the east of a shopping center.

The route heads into commercial Center City Allentown, intersecting the northern terminus of northbound PA 222 at West Walnut Street, which is one-way eastbound.

Past the arena, the route intersects West Linden Street, which is one-way westbound and serves as the southbound beginning of PA 222.

Continuing north, PA 145 leaves Center City Allentown and passes through urban areas of homes and businesses, intersecting Tilghman Street.

The route widens to four lanes and crosses over Sumner Avenue on a bridge, at which point it leaves Allentown for Whitehall Township.

Here, the route becomes four-lane divided MacArthur Road and intersects Mickley Road/6th Street as it heads into commercial areas.

The road crosses Jordan Creek and passes between businesses to the west and residential areas to the east before it comes to an interchange with the US 22 freeway.

Past this interchange, PA 145 becomes a six-lane divided highway with a Jersey barrier and several intersections controlled by jughandles.

PA 145 continues past shopping centers and businesses, intersecting Schadt Avenue and curving to the northwest.

The route continues through wooded areas with some nearby farms and residential commercial development, crossing Coplay Creek.

The route intersects Second Street and narrows to a two-lane undivided, unnamed road as it heads along the west bank of the Lehigh River.

The road continues through wooded areas alongside the river before it curves northwest away from it and reaches the community of Laurys Station.

Past this, PA 145 heads south on two-lane undivided Riverview Drive and passes through a mix of farms and homes to the west of the river and the railroad tracks.

The road begins a long curve to the west and then to the northwest as it continues parallel to the Lehigh River, heading into wooded areas with some development.

The route passes through the community of Lockport and runs west through a mix of farms and woods before it enters the borough of Walnutport.

The route heads into commercial areas, briefly becoming a divided highway before intersecting Main Street, where the name changes to North Best Avenue.

[11] Following the completion of the US 22 freeway in 1955, the southern terminus of PA 145 was cut back to the cloverleaf interchange with I-78/US 22 in Whitehall Township.