The idea took shape in the 1990s, when Mobile and Alabama state leaders formed a nonprofit to create a maritime museum that could serve as an educational anchor for the region. Mayor Mike Dow championed the project as the centerpiece of "Mobile Landing," a downtown waterfront development meant to restore public access to the river. The museum opened on September 26, 2015, and was quickly named "Attraction of the Year" for 2016 by the Alabama Department of Tourism. It holds a distinction no other institution can claim: it is the only fully interactive maritime museum in the world and the only museum dedicated specifically to the Gulf of Mexico.

The museum's board chose to house exhibits inside a full-sized container ship replica because Mobile is where container shipping technology was born. The replica, dubbed the SS McLean, sits surrounded by water and is designed to look as if it is floating at dockside. Interior walkways mimic those of actual large vessels. Visitors walk through multiple decks exploring 90 exhibits that cover hurricanes, shipwrecks, offshore drilling, sailing, and the mechanics of maritime navigation. One simulator lets visitors choose a vessel and try to navigate through the Gulf into Mobile's port, using images designed to represent real locations along the waterway. The building also houses Mobile's only waterfront restaurant and a gift shop, both carrying a nautical theme.

One of the museum's more unexpected exhibits lines the rampways on either side of the container ship: panels explaining common English phrases that originated at sea. "All in a Day's Work," "Clean Bill of Health," "Cup of Joe," "Out of the Blue," "Lay of the Land" - each saying gets its maritime origin story revealed. The exhibit earned the Downtown Innovation Award from the Downtown Mobile Alliance in 2015. The museum's founding executive director, Tony Zodrow, was named Maritime Person of the Year by the Propeller Club of the Port of Mobile in 2016, recognition of the years of effort required to bring the project from concept to completion.

The museum's identity has proven nearly as turbulent as Gulf waters. Originally bearing the Congressionally designated name National Maritime Museum of the Gulf of Mexico, it rebranded to GulfQuest before opening. Low attendance forced a temporary closure in November 2016; it reopened in February 2017 with city-provided staffing. In April 2024, the museum changed its name back to the National Maritime Museum of the Gulf of Mexico at a cost of nearly $100,000. In February 2025, the Mobile City Council approved $740,000 to settle the museum's outstanding exhibit-related debt. The museum has plans for a Jimmy Buffett exhibit and an interactive display about the Mobile-Tensaw River Delta. Despite the churn, the institution endures - four executive directors deep and still telling the Gulf's story.