PA 443 begins at an intersection with SR 3009 (North Front Street) on the east bank of the Susquehanna River in the community of Fort Hunter in Middle Paxton Township, Dauphin County, heading northeast on Fishing Creek Valley Road, a two-lane divided highway.

Shortly after beginning, the route comes to a partial cloverleaf interchange with the US 22/US 322 freeway and passes over Norfolk Southern's Buffalo Line on a bridge.

PA 443 passes to the north of the Boyd Big Tree Preserve Conservation Area and continues through the narrow valley with some fields and residences, crossing into West Hanover Township.

Past this intersection, the route passes to the north of Hollywood Casino at Penn National Race Course as it continues northeast.

[2][3] PA 443 crosses into East Hanover Township in Lebanon County and continues through agricultural areas with some homes to the south of Blue Mountain, gaining a second westbound lane past the Pleasant View Road intersection.

The route narrows to two lanes and becomes Clement Avenue, passing to the northwest of Memorial Lake State Park before it enters the grounds of the Fort Indiantown Gap military reservation.

The road crosses the Appalachian Trail again and forms the northwestern border of Swatara State Park, curving northeast and running through forests with some farmland and residences and passing through the community of Murray.

PA 443 comes to an interchange with I-81 near businesses and continues east through a mix of farm fields and woodland with some residential and commercial development, running through the community of Exmoor.

The road intersects the northern terminus of PA 645 before it makes a curve to the north and enters the borough of Pine Grove.

Farther east, the route enters Wayne Township and becomes Long Run Road, continuing through agricultural land with some homes.

PA 443 curves northeast and continues along Columbia Street before it turns northwest onto Parkway, a two-lane divided highway with a wide median that passes through residential areas.

[2][5] PA 443 leaves Orwigsburg for West Brunswick Township and becomes Chestnut Road, passing through a mix of farmland and woodland with some homes and heading to the east.

The road crosses the Little Schuylkill River into the borough of New Ringgold and becomes Hughes Avenue, heading southeast past residences and businesses.

The route runs between the railroad tracks to the west and homes to the east before it curves northeast through forested areas parallel to the Little Schuylkill River.

PA 443 heads back into East Brunswick Township and becomes Clamtown Road, winding northeast through a mix of farm fields and woods.

[2][5] The road crosses into Mahoning Township in Carbon County and becomes Blakeslee Boulevard Drive West, continuing northeast through agricultural areas with some woods and residences.

Farther northeast, PA 443 becomes Blakeslee Boulevard Drive East and runs through a mix of woodland and commercial development, passing to the north of the Carbon Plaza Mall.

In addition, the route was widened to a multilane road between the border of Dauphin and Lebanon counties and Fort Indiantown Gap.