I-10 enters Louisiana at the state's southwestern corner from Orange, Texas, in a concurrency with US Route 90 (US 90), which leaves the freeway at the first exit.

I-10 crosses the Calcasieu River Bridge into Lake Charles, passing north of the center of town, before meeting the western end of I-210.

In Lafayette, I-10 meets the current southern terminus of I-49, leaving northwest out of the city and passing by the community of Breaux Bridge.

This route has signs and is designated as an alternate I-10 bypass that runs from I-10/I-49 north to US 190 (exit 19B at Opelousas) then east across to Baton Rouge and back down to I-10 via I-110 south.

In the capital of Baton Rouge, US 190 continues east alongside I-12 to Hammond and Slidell while I-10 turns southeastward and parallels US 61 (Airline Highway) to New Orleans.

[4] By c. 1943, it had been shifted to the north west of New Orleans, using the Louisiana Highway 12 (LA 12), US 190, and US 61 corridors, and serving Baton Rouge but not Lake Charles or Lafayette.

[7] Prior to the gaining of federal funding for the Interstate System in the late 1950s, a toll road, the Acadian Thruway, had been proposed between Lafayette and a point near Gramercy on Airline Highway (US 61).

In addition, the two major bridges on the route in Calcasieu Parish between the Texas state line and Lake Charles were built for US 90 in the early 1950s and retrofitted for I-10 traffic.

By the spring of 1975, the entire route of I-10 had been opened across Louisiana except for a problem 5.5-mile (8.9 km) section between Gonzales and Sorrento that was not completed for another three years.

Unlike the Escambia Bay Bridge (east of Pensacola, Florida and damaged by Hurricane Ivan), which is a major artery, I-12 is available to bypass New Orleans.

On January 6, 2006, at 6:00 am, both lanes of the westbound span were reopened to traffic using temporary metal trusses and road panels to replace damaged sections.

[57] In 2014, the Louisiana State Legislature officially named the Twin Span as the Frank Davis "Naturally N'Awlins" Memorial Bridge.

[citation needed] In 2012, the state completed a widening project between Causeway and Clearview Parkway and between the I-10/I-610 split and Airline Highway (US 61).

[citation needed] On April 8, 2017, Louisiana DOTD broke ground on the reconstruction of seven miles (11 km) of I-10 between I-49 (exit 103) and the Atchafalaya Basin.

[60] In order to reduce the amount of congestion for travelers trying to reach the Louis Armstrong New Orleans International Airport, flyover ramps were constructed at the I-10 and Loyola Drive Interchange in Kenner.

Instead, in October 2022, the governments of Louisiana and New Orleans introduced a $94.7 million proposal to improve the elevated freeway and the space beneath it as well remove four ramps in Tremé.