The east end is in the middle of the George Washington Bridge over the Hudson River in Fort Lee, Bergen County, while the route is concurrent with I-95 and US 1-9.

US 46 begins at a complex interchange with I-80 and Route 94 near the Portland–Columbia Toll Bridge leading to PA 611 in the community of Columbia in Knowlton Township, Warren County.

From this interchange, the route heads southeast along the east bank of the Delaware River as a four-lane divided highway briefly before narrowing into a two-lane undivided road.

From here, the route continues alongside the river, passing more rural areas of woods and farms with occasional development as it enters White Township.

US 46 makes a sharp turn to the east away from the Delaware River, widening into a four-lane divided highway again as it bypasses the town of Belvidere and has a few businesses on it.

[1][2] From this point, the route continues east through dense woods prior to turning northeast into Liberty Township.

Here, US 46 enters more agricultural areas and turns east again, with development increasing along the road as it passes through Great Meadows-Vienna.

It continues into Mount Olive Township, taking a sharp turn to the east before the road becomes undivided while remaining four lanes.

From this point, the route narrows back into a two-lane undivided road and runs through developed areas of Netcong a short distance to the south of NJ Transit's Morristown Line/Montclair-Boonton Line.

[1][2] At a three-way intersection which was formerly Ledgewood Circle, Route 10 begins straight while US 46 turns left to continue east as a two-lane undivided road through more development, crossing the Dover and Rockaway River Railroad's High Bridge Branch.

The road widens to four lanes as Blackwell Street splits from it at an eastbound exit and westbound entrance prior to a bridge over the Rockaway River and NJ Transit's Morristown Line/Montclair-Boonton Line.

[1][2] The road is lined with a moderate number of businesses, most with right-in/right-out (RIRO) access, as it continues southeast through Denville, narrowing to four lanes before coming to an interchange with Route 53.

Shortly farther along US 46, Route 159 and CR 627 meet it at a traffic light-controlled intersection, providing cross-traffic and turns onto US 46.

US 46 has an exit for Van Houten Avenue/Grove Street before coming to a large interchange with the southern terminus of the Route 19 freeway, CR 509, and the Garden State Parkway.

US 46 then begins a brief concurrency with Piaget Avenue in Clifton with a series of connector streets and three intersections controlled by stoplights.

After the split, US 46 turns into a limited-access road again and passes under Main Avenue/CR 601 and Norfolk Southern's Passaic Spur line before coming to an interchange with the northern terminus of the Route 21 freeway.

[1][2] US 46 turns east and crosses the Passaic River a fourth and final time, entering Bergen County in Elmwood Park.

Passing through more RIRO-accessed business areas, the road narrows to four lanes and has a partial interchange with the Garden State Parkway.

Past the parkway, US 46 continues as a road with some jughandles and other traffic light-controlled intersections (but still largely maintaining RIRO access to driveways and side streets), crossing New York, Susquehanna and Western Railway's Dundee Branch line and passing through a small corner of Garfield before crossing into Saddle Brook.

Within Saddle Brook, the road turns more to the southeast and crosses over NJ Transit's Bergen County Line.

A short distance later, US 46 reaches an interchange with Route 17 and crosses NJ Transit's Pascack Valley Line near the Teterboro station.

In Ridgefield Park, the route is called Winant Avenue and becomes a four-lane divided highway before briefly becoming undivided again.

Past this interchange, the route widens to six lanes and crosses the Overpeck Creek into Ridgefield, where it passes over CSX's Northern Running Track railroad line into the Morsemere neighborhood.

US 1-9 / US 46 continue into Fort Lee, where it has access to a couple commercial areas via RIRO before encountering the northern terminus of Route 63 at a westbound exit and eastbound entrance.

From here, the highway becomes a surface road that continues past more businesses and homes with RIRO access, angling northeast as it comes to an exit for Main Street.

By 1920, the portion of the modern route west of Hackettstown was signed as an easterly extension of the Lackawanna Trail, running through Pennsylvania to Binghamton, New York.

Pre-1927 Route 10, which was legislated in 1917, continued east on Market Street on the other side of Paterson to Edgewater, where it connected to the Fort Lee Ferry across the Hudson River.

[18][19] In December 1937, a section of highway was opened from the Passaic River at Clifton to Hasbrouck Heights, marking the completion of Route 6 with the exception of the Paterson bypass.

[42] In 1988 the Legislature resolved that "The Commissioner of Transportation shall designate that portion of United States Highway Route 46 located between Hope Road and Barkers Mill Road in the township of Independence, Warren County as 'Clifford Jones Avenue'," honoring United States Army Specialist Clifford Jones, Jr., a resident of Independence Township who had been killed in action in 1968 during the Vietnam War.

[46] The proprietors at the site also claim to have lost a significant amount of business due to reduced accessibility to their establishments, caused by the redesign and loss of the former circle.