From the southern terminus, the road heads between the Susquehanna River to the west and homes and businesses to the east, coming to the end of northbound PA 61 Truck at Arch Street.

The route continues north along the east bank of the river through residential areas, passing the site of Fort Augusta.

A short distance later, PA 405 turns north and comes to a bridge over the Susquehanna River, heading onto Packer Island.

Here, the route becomes a three-lane road with a center left-turn lane called Bridge Avenue and runs past homes and industrial areas to the east of Shikellamy State Park.

The road narrows to two lanes and curves northwest, heading off the island and over the Susquehanna River into the borough of Northumberland.

PA 405 becomes King Street and crosses the North Shore Railroad, running past homes and businesses and to an intersection with US 11.

PA 405 splits from US 11 by turning northwest onto Duke Street, heading through residential and commercial areas.

[3] The route leaves Northumberland for Point Township and splits from Duke Street, following Susquehanna Trail and running between wooded areas near the Buffalo Line to the southwest and the residential community of Kapp Heights to the northeast.

PA 405 continues through fields and woods with some development and curves to the north-northwest, passing to the west of Montour Ridge.

The route reaches the center of Chillisquaque, where it turns westward for a distance through an isolated area along the West Branch Susquehanna River.

The route meets the shoreline, where PA 405 turns to the northwest along a rural, unpopulated stretch of West Chillisquaque Township.

North of East Lewisburg, PA 405 passes a large farmland plot before leaving the shoreline of the Susquehanna West Branch.

The route returns to the shoreline of the West Branch of the Susquehanna River, continuing northward along the Turbot Hills Golf Course.

The route continues northward along the West Branch of the Susquehanna River, passing a large industrial complex before reaching a merge in the railroad tracks.

The surroundings of the highways are highly populated, and the two routes continue in Watsontown until an intersection with East 11th Street, when the two roads leave the community.

PA 405 continues northward, bypassing around Dewart and crossing the railroad tracks it had been paralleling for the distance.

In Muncy, the highway heads to the southeast along Water Street into the community center, where it turns to the northeast.

PA 405 continues farther, intersecting with local roads, running along South Main Street for a distance, entering the borough of Hughesville, where the highway becomes densely populated.

The bridge over the West Branch of the Susquehanna River was originally privately maintained, with the charter for its construction coming down from the Pennsylvania State Legislature on March 13, 1835.