The highway acts as a connector between several major urban areas, including Miami, Orlando, Ocala, Gainesville, Athens, and Knoxville.

It also crosses the Great Smoky Mountains National Park, where it meets the southwestern end of the Blue Ridge Parkway, and where no trucks or other commercial traffic are allowed.

The route parallels Interstate 95 north out of Miami to western Aventura, where I-95 heads northeast to access Fort Lauderdale and the remainder of the eastern Florida coast.

Additionally, US 441 meets Interstate 595 (Exits 8 and 8B) west of Fort Lauderdale and the tolled State Road 869 (the Sawgrass Expressway) in Coconut Creek.

US 441 continues west to the eastern shore of Lake Okeechobee, where it turns north to follow the shoreline to Pahokee.

US 441 continues north, meeting the Turnpike at Yeehaw Junction (via State Road 60) prior to intersecting U.S. Route 192 at Holopaw.

US 441 continues to the northwest, passing across Paynes Prairie Preserve State Park, through Gainesville and interchanging with Interstate 75 (Exit 399) ahead of an intersection with US 41 in High Springs.

Past Lake City, US 441 interchanges with Interstate 10 (Exit 303), then skirts the western edge of the Okefenokee Swamp as it enters Georgia.

In Georgia, US 441 continues to bypass the Okefenokee Swamp to Edith, where it turns to the northwest toward the interior of the state.

North of the city, US 280 splits off while US 319 and US 441 then pass Little Ocmulgee State Park before continuing concurrently to Dublin.

US 129 and US 441 continue concurrently through Madison (where US 129 and US 441 interchange with Interstate 20) and U.S. Route 278 to Athens, where US 129 and US 441 turn eastward onto a limited-access beltway encircling the city.

The portion of US 23 / US 441 from U.S. Route 123 west of Toccoa to the North Carolina state line is located within the Chattahoochee National Forest.

US 23 and US 441 turn east, briefly overlapping US 64 around Franklin before separating from the route and continuing to the northeast through the forest.

From the park entrance to the Tennessee state line, the route follows a northwesterly alignment as it traverses the Great Smoky Mountains.

In 1952 US 441 reached its final configuration when it was extended north from Baldwin to Rocky Top, Tennessee (then known as Lake City).

This prompted an urban legend that stated that song was based on a suicide committed on the university campus.

He sings, "Its time to show myself the door/ There's no pretending anymore/ No, it's over/ Where I'm going I don't know/ Somewhere down this dusty road/ North on 441/ Pass the rolling cattle fields, the trailer parks, and rusted cotton mills/ Lord get me out of here."