The southern terminus of the route is at US 90 in Bayou Sauvage National Wildlife Refuge in eastern New Orleans, Louisiana.

The Maestri Bridge, which carries US 11 across Lake Pontchartrain, served as the only route to New Orleans from the east for six weeks after Hurricane Katrina due to its sturdy construction.

The route begins as a two-lane highway that travels northward through a remote stretch of marshland within both the Bayou Sauvage National Wildlife Refuge and the New Orleans city limits.

Upon reaching the north shore, US 11 follows Pontchartrain Drive into the city of Slidell, where it becomes a busy four-lane commercial corridor.

[12][13] After a brief concurrency with Louisiana Highway 433 (LA 433), US 11 turns onto Front Street and travels alongside the Norfolk Southern Railway (NS) line through Slidell's historic district.

During this stretch, the route intersects both US 190 Business (Fremaux Avenue) and mainline US 190 (Gause Boulevard), both four-lane thoroughfares connecting with nearby I-10.

Returning to two-lane capacity, US 11 crosses to the west side of the NS line on a narrow overpass built in 1937.

Following a second interchange serving the small town, I-59 and US 11 cross the West Pearl River into the dense Honey Island Swamp.

Along this stretch is an exit connecting to Old US 11, a remnant of the pre-Interstate alignment that provides access to Pearl River Wildlife Management Area.

US 11 generally parallels I-59 across Mississippi, serving as a local business route and following city streets through communities such as Hattiesburg, Laurel, and Meridian, where I-59 begins a concurrency with I-20 eastbound.

US 11 passes through Gadsden and Fort Payne before crossing into Georgia 10 miles (16 km) northeast of Hammondville.

The routes briefly overlap with US 41, here concurrent to US 76, on Dodds Avenue before resuming an easterly progression on Brainerd Road thereafter called Lee Highway.

US 11 remains close to I-75 as it heads north, passing through Athens, Sweetwater, Loudon, and Lenoir City before entering Farragut.

On the western edge of town, US 11 merges with US 70 at Dixie Lee Junction to form Kingston Pike.

Part of the Carolina Road, a colonial trail, follows the roadbed of US 11, also known as the Lee Highway, through Virginia.

Near Cloverdale is the historical marker: "This is the old road from Pennsylvania to the Yadkin Valley, over which in early times settlers passed going south.

"[16] From Roanoke, the highway continues through Buchanan, Lexington, Staunton, Harrisonburg, and Winchester in the Shenandoah Valley.

US 11 heads northeast for about 35 miles (56 km) through Berkeley County, passing through Inwood, Martinsburg, and Falling Waters before crossing the Potomac River into Maryland.

In Maryland, US 11 passes over the Potomac River into Williamsport and through Hagerstown in Washington County before crossing the Mason–Dixon line into Pennsylvania.

Known as the Molly Pitcher highway, US 11 follows I-81 northeast through the Cumberland Valley, running parallel to each other as they pass through Chambersburg, Shippensburg, and Carlisle.

US 11, in contrast, continues to parallel the main Susquehanna River, passing through municipalities such as Danville, Bloomsburg, and Berwick prior to reaching Wilkes-Barre.

US 6 joins US 11 westward to Factoryville, where US 11 separates from US 6 and resumes its northerly trek through Susquehanna County to the New York–Pennsylvania border.

US 11 heads northeast from Watertown, passing along the northern edge of Fort Drum and traversing a number of towns and villages, including Canton and Potsdam.