After heading north through LaPlace to a junction with Interstate 10 (I-10) west of New Orleans, the highway joins I-55 on a 22-mile-long (35 km) twin-span viaduct across the Manchac Swamp.

For the remainder of its journey in southeastern Louisiana, the route closely parallels I-55, which carries the bulk of through traffic toward Jackson, Mississippi and points north.

US 51 serves local traffic through a string of communities in Tangipahoa Parish situated along the Canadian National Railway line, including the towns of Independence, Amite City, and Kentwood.

From the south, US 51 begins at an intersection with US 61 (West Airline Highway) in Laplace, an unincorporated community located on the east bank of the Mississippi River in St. John the Baptist Parish.

US 51 heads northeast as an undivided four-lane highway with a center turning lane through a growing residential and commercial corridor.

With a median replacing the center lane, US 51 proceeds a short distance to an intersection with Frenier Road, where signage directs through traffic to turn west and follow a ramp onto the elevated I-55 at exit 1.

7 miles (11 km) along the way, a tight diamond interchange at Ruddock connects with the grade-level pre-interstate alignment, which serves as a frontage road and closely parallels the entire stretch.

The area flanking the pass, generally called Manchac, contains a cluster of boat houses and fishing camps situated along the frontage road.

[3][5][6] Heading north on Morrison Boulevard, US 51 returns to its original capacity, an undivided four-lane highway with center turning lane.

[3][5][6] After passing through the community of Natalbany, US 51 enters the village of Tickfaw and begins to follow alongside the Canadian National Railway (CN) line.

4 miles (6.4 km) north of Tickfaw, US 51 passes through the town of Independence, where LA 40 connects to I-55 as well as points such as Loranger and Husser.

[3][5][6][7] Between two points known as Arcola and Fluker, located just north of the neighboring town of Roseland, US 51 has a 3-mile-long (4.8 km) concurrency with LA 10, another connection to Franklinton as well as Greensburg.

US 51 passes through Kentwood on 3rd Street and intersects LA 38, the main east–west thoroughfare, at Avenue G. The highway curves to the northeast on the way out of town and continues for another 4 miles (6.4 km) to the state line.

[3][5][7] The portions of US 51 not concurrent with I-55 are generally classified as an urban or rural major collector by the Louisiana Department of Transportation and Development (La DOTD).

[10] It was the main traffic route connecting New Orleans to Jackson, Mississippi and Memphis, Tennessee in the days before the existence of the Interstate Highway System.

This proposed scenic highway was never fully realized, and US 51 effectively followed the route of US 61 through the New Orleans area until being truncated to its present terminus in LaPlace in 1951, eliminating the concurrency.

In New Orleans, Route 33 was designated to follow an existing road alongside a shipping canal from South Carrollton Avenue to an area on Lake Pontchartrain known as West End.

The construction of the lakeshore highway was intended to provide a direct land connection between New Orleans and Hammond while taking advantage of the scenic beauty of Lake Pontchartrain and the surrounding swampland.

In addition, the man-made embankment required to carry the road would serve as a levee to prevent lake water from inundating the extensive residential development envisioned to line the highway.

Nevertheless, the highway distance between New Orleans and Hammond was reduced from 90.5 to 68 miles (145.6 to 109.4 km) by eliminating a circuitous route around the eastern side of Lake Pontchartrain through Slidell, Mandeville, and Covington that included two ferry crossings.

[20] The route through the LaBranche swamp in St. Charles Parish proved to be the most difficult road construction in the state up to that time,[21] and the heavy expenditure invested became a continual source of controversy.

A two-mile section of the embankment, not yet surfaced for travel, was severed to provide a path for floodwaters as part of a larger system designed to prevent a re-occurrence of the Great Mississippi Flood of 1927.

[20] Over the next few years, a new levee system was constructed by improved methods on the land side of the original embankment, which was then abandoned as a public road.

[33] On September 13, 1976, two barges veered from the main channel below the Pass Manchac Bridge, striking a bent leading to the collapse of three spans.

The final realignment of US 51 to date shifted the route through LaPlace from Main Street, a narrow two-lane thoroughfare, onto a parallel five-lane alignment completed in 1985.

[39][40] La DOTD is currently engaged in a program that aims to transfer about 5,000 miles (8,000 km) of state-owned roadways to local governments over the next several years.

[41] Under this plan of "right-sizing" the state highway system, the portion of US 51 between I-55 and US 190 in Hammond is proposed for deletion as it does not meet a significant interurban travel function.

It branches to the north as an undivided two-lane highway alongside the Canadian National Railway (CN) line through the thickly wooded swamp into Ponchatoula, traveling on Southwest Railroad Avenue.

After two miles (3.2 km), the highway reaches the center of town and intersects LA 22 (West Pine Street), an undivided four-lane thoroughfare.

[5][6][44] Shortly afterward, the highway passes through a diamond interchange with I-12, a northern bypass of the New Orleans metropolitan area connecting with Baton Rouge and Slidell.