U.S. Highway 11 in Louisiana extends from the national southern terminus in New Orleans for 31 miles (50 km) to the Mississippi state line south of Picayune, Mississippi.

From the south, U.S. 11 begins at an intersection with U.S. 90 (Chef Menteur Highway) in Eastern New Orleans, near the community of Venetian Isles. U.S. 11 heads northward, paralleling Interstate 10 (I-10) through the community of Irish Bayou, until the highways cross at an interchange (Exit 254) at a point on Lake Pontchartrain known as Point aux Herbes. I-10 proceeds northeast onto the Twin Spans, while U.S. 11 continues north onto the Maestri Bridge, locally known as the Highway 11 Bridge or Five Mile Bridge.

About midway across Lake Pontchartrain, U.S. 11 crosses from Orleans Parish into St. Tammany Parish. U.S. 11 then makes a turn to the northeast, paralleling I-10 to the west, and makes landfall in the community of North Shore, gaining the local name of Pontchartrain Drive. U.S. 11 continues northeast through Eden Isle and enters Slidell, becoming that city's primary north-south arterial. In Slidell, U.S. 11 intersects Louisiana Highway 433 (LA 433) (Old Spanish Trail), its former alignment. Turning northwest, U.S. 11 and LA 433 become concurrent for a short distance until reaching Front Street, where U.S. 11 turns to the northeast.

U.S. 11 continues on Front Street through Slidell's historic district, running along the east side of the Norfolk Southern railroad tracks. At Fremaux Avenue, U.S. 11 intersects U.S. 190 Business, and the two highways become concurrent for several blocks until the intersection with mainline U.S. 190 at Gause Boulevard. Here U.S. 190 Business reaches its western terminus, and U.S. 11 continues northward along Front Street. Just north of Indiana Avenue, a local street, U.S. 11 crosses the Norfolk Southern line via an overpass. Returning to grade, U.S. 11 now continues northward along the west side of the railroad tracks. Reaching the northern limit of Slidell, U.S. 11 enters a partial cloverleaf interchange with I-12 (the West Florida Republic Parkway) at Exit 83. After passing through the sparsely-developed communities of North Slidell and Alton, U.S. 11 intersects LA 1091 (Robert Boulevard) just north of Highway Department Road.

Upon reaching the town of Pearl River, U.S. 11 intersects LA 41 (Watts Road) and LA 3081 (Main Street) at the southern terminus of both highways. Here, U.S. 11 turns southeast briefly to an interchange with I-59, also the northern terminus of LA 1090. U.S. 11 continues north onto I-59 at Exit 3, utilizing the interstate's alignment for the remainder of the distance in Louisiana. An interchange at Exit 5A forms the northern terminus of LA 3081, the pre-interstate alignment of U.S. 11. I-59 and U.S. 11 proceed northward, crossing the West Pearl River and leaving the town of Pearl River. Just north of the bridge is Exit 5B, an interchange with a local road known as Old U.S. 11, also part of the former alignment. I-59 and U.S. 11 continue northward through the Honey Island Swamp, reaching the final interchange, Exit 11 (Pearl River Turnaround), before crossing the state line into Mississippi.

The original 1926 southern terminus of U.S. 11 was in Santa Rosa, Mississippi at a junction with U.S. 90, the present intersection of MS 607 and Old U.S. 11. In 1935, the Rigolets-Pearlington Cutoff was opened, shortening the distance from New Orleans to the Mississippi Gulf Coast by 22 miles. Once U.S. 90 was officially shifted onto the cutoff in 1937, U.S. 11 was briefly extended south to meet it. The following year, U.S. 11 was re-routed into Louisiana along the former route of U.S. 90. From its original southern terminus in Santa Rosa, U.S. 11 then followed what is now Old U.S. 11 to Pearl River, current U.S. 11 to Slidell, and LA 433 to U.S. 90 at the Rigolets Bridge. U.S. 11 was co-signed with U.S. 90 from that point to a new southern terminus at the intersection of Canal and North Broad Streets in Downtown New Orleans.

In December 1938, the state of Louisiana purchased the Watson-Williams toll bridge, also known as the Pontchartrain Bridge, across eastern Lake Pontchartrain. It was immediately made a free bridge and renamed for New Orleans' mayor, Robert S. Maestri. In 1939, U.S. 11 was moved onto its current alignment over the bridge (now commonly referred to as the Highway 11 Bridge or Five Mile Bridge), still co-signed with U.S. 90 to Canal and Broad in New Orleans. The Michoud Cutoff, an eastern extension of Chef Menteur Highway, was opened in May 1942, slightly shortening the route of U.S. 11-90 and eliminating two grade crossings. In 1951, U.S. 11 was cut back to its current southern terminus at U.S. 90 near Irish Bayou.

In July 1963, construction of I-59 was completed from Pearl River north across the Louisiana-Mississippi state line with the opening of the I-59 West Pearl River Bridge. The following year, the parallel U.S. 11 West Pearl River Bridge was closed due to safety reasons, and U.S. 11 assumed its current routing co-signed with I-59 between Pearl River and Nicholson, Mississippi.