The western part of the route runs through suburban areas of Morris and Essex counties, crossing the Watchung Mountains.

I-280 intersects several roads, including the Garden State Parkway in East Orange and Route 21 in Newark.

I-280 begins at the interchange with I-80 and US 46 in Parsippany–Troy Hills, Morris County, and heads southeast into wooded surroundings as a four-lane freeway.

[1] The freeway runs near some fields before heading back into woods and entering Roseland, Essex County, at the crossing of the Passaic River.

[1] At this point, the roadway widens to six lanes and runs near wooded suburban areas, passing over the Morristown and Erie Railway's Whippany Line before reaching CR 527 at another cloverleaf interchange.

After Prospect Avenue (CR 577), I-280 makes a sharp turn to the south and goes through the First Watchung Mountain in another cut, resuming into suburbs again and heading south-southeast as it intersects Mt.

Here, I-280 narrows back to six lanes and heads onto a depressed alignment with frequent overpasses, running a short distance to the south of NJ Transit's Morristown Line.

As the road returns to surface level and begins to parallel NJ Transit's Morris & Essex Lines and Montclair-Boonton Line to the north, an unused bridge carries the western end of the 1954 section of freeway over the railroad to Orange Street east of Duryea Street.

Past CR 508, the freeway narrows to four lanes and comes to the toll plaza for the New Jersey Turnpike (I-95) at exit 15W, at which point I-280 ends.

The first was whether to build the highway on an elevated or depressed alignment through urbanized areas of East Orange and Newark.

Much of the material that was excavated from this section of I-280 and east was removed via a temporary rail line that was built in the center of the right-of-way west to Interstate 80.

[15][16] The construction of I-280 destroyed a large part of the historic urban cores of Orange, East Orange, and Newark, while providing a path for shoppers to head to shopping malls in surrounding suburban communities rather than shop in aging downtowns that had been disrupted by the highway construction.

In 2001, the state determined the Stickel Bridge over the Passaic River and its approaches were structurally deficient and was going to need to be replaced after sections of it were falling apart.

[4][27][28] Instead of replacing the bridge, in 2007, the New Jersey Department of Transportation (NJDOT) decided to rehabilitate it at a lower cost.

[31] Replacement of partial access in central Harrison with service roads, a new interchange, and an overpass (to improve access to Harrison Avenue, the PATH station, and Sports Illustrated Stadium, and to give north–south passage to local street traffic) is in the planning stages.