The idea for a trans-peninsula highway that connected the west and east coasts of Florida originated in April 1915 at an informal meeting in Tallahassee between Francis W. Perry, then president of the Fort Myers Chamber of Commerce, and James F. Jaudon of Miami, after which they returned to their respective cities and began advocating for the construction of what was originally called the Miami to Marco Highway.

At a subsequent meeting in Orlando, on June 10, 1915, of what became the Central Florida Highway Association, Perry introduced a resolution which was seconded by Tampa's E. P. Dickie, for the construction of the "Tamiami Trail", which was to run from Tampa through Riverview, Bradenton, Sarasota, Arcadia, Punta Gorda, Fort Myers, Estero, Bonita Springs, Naples, Marco, then east directly across the state to Miami.

The team consisted of Hobart Crabtree (county engineer), James F. Jaudon, L. T. Highleyman, Van Cleve Hallowes, Wallace Culbertson, Walter Ludlam, J. T. Albritton, A. W. Frederick and one helper.

The following year, Barron Collier, an advertising mogul who had recently diversified his holdings by investing in various types of businesses and millions of acres of southwest Florida wilderness, pledged that he would bankroll the completion of the Tamiami Trail; in return, the State legislature would establish a new county and name it after him.

The Tamiami Trail Blazers would launch an expedition leaving out of Fort Myers on April 4, 1923, with the goal of reaching Miami.

It would consist of a motorcade of 10 vehicles, a commissary truck, 7 Ford Model T's, an Elcar[5] and a tractor, conveying 29 people (25 men and 4 women).

[10] To celebrate, a convoy of over 500 cars would leave out of Tampa on the morning of April 25 and arrive in Miami during the late part of the next day.

At the time it was considered a major achievement of engineering that was the only route from Naples (and, by extension, from Tampa) to the southeastern coast of Florida.

In 1965, US 41 was rerouted as a bypass along unsigned SR 45A around Venice Gardens, while Business US 41 signs grace the three-mile-long (4.8 km) former alignment (which is still named Tamiami Trail).

Also in 1968, construction of an extension of Interstate 75 (I-75) south from Tampa to Miami was started, with an eye toward routing the freeway along an upgraded Tamiami Trail from Naples to a soon-to-be completed SR 836 whereupon it would continue on the east–west highway to its intended terminus at an interchange with I-95.

Yet, according to the United States Army Corps of Engineers, this was only a partial solution to the problems of the Everglades and the Tamiami Trail.

[13] In 2003, after considering a variety of plans involving the rebuilding of US 41/SR 90, the Corps recommended that a 3,000-foot-long (910 m) causeway be built near the Northeast Shark Slough northeast of Everglades National Park, all road fill removed that would otherwise be adjacent to the bridge, the 57 culverts that are already in place maintained, and the appropriate water flow rate maintained under the non-causeway portions of the Tamiami Trail crossing the Everglades.

[14] The proposed causeway is being called the Everglades Skyway by the Sierra Club, Audubon Society, World Wildlife Fund, and other organizations in an Internet-based effort to lobby Florida and United States government officials for project construction money.

[15] In December 2009, construction began on a one-mile-long (1.6 km) project to lift a portion of the road to allow the more natural water flow into the southern Everglades.

[16][17] At the Everglades Foundation's America's Everglades Summit held in mid-May 2010, Assistant Secretary of the U.S. Department of Interior, Thomas Strickland, revealed that the Interior Department's National Park Service released a draft Environmental Impact Statement recommending an additional 5.5 miles (8.9 km) of bridging the Tamiami Trail.

[19] In June 2019, a $60 million grant was announced by the Federal Highway Administration (FHWA) to Everglades National Park through the Nationally Significant Federal Lands and Tribal Projects program to complete the Tamiami Trail Next Steps project, intended to allow more north-to-south water flow into the Everglades.

This grant matches a $43.5 million commitment by the State of Florida for the raising and reconstruction of the remaining 6.5 miles (10.5 km) of the eastern Tamiami Trail roadway.