The highway's northern terminus is east of Copper Harbor, Michigan, at a modest cul-de-sac near Fort Wilkins Historic State Park at the tip of the Keweenaw Peninsula on Lake Superior in the state's Upper Peninsula. Its southern terminus is in Miami, Florida, at an intersection with Brickell Avenue (U.S. Route 1).
It closely parallels Interstate 75 from Naples, Florida, all the way through Georgia to Chattanooga, Tennessee.
In Florida, Highway 41 is paralled by Interstate 75 all the way from Georgia (on the northern border) to Miami, and I-75 has largely supplanted US-41 as a major highway.
Between Miami and Naples, US 41 runs through the vast Everglades wilderness. This section has been designated a National Scenic Byway. The byway runs east-west along most of this stretch through the Big Cypress National Preserve, skirting the northern border of the Everglades National Park for about 20 miles. This section of the highway is known as the Tamiami Trail (derived from the combination of Tampa and Miami, the road's two termini).
US 41 is in the process of being widened throughout the northern Tampa Bay suburbs. It is currently six-lanes wide between Tampa, Lutz, Florida, and much of Land O' Lakes, and again between Garden Grove and Brooksville, Florida. It is also four lanes wide in Tampa south of BUS US 41, between a section north of Land O' Lakes, Masaryktown, and Garden Grove, Florida, and south of Inverness, Florida. A large portion of US 41 is co-designated along the unmarked Florida State Road 45 between Belle Meade and High Springs, Florida.
From US 92 in Tampa to US 41 Business and State Road 676 near the unincorporated Palm River-Clair Mel, US 41 carries the unsigned State Road 599 designation. It contains the northwestern end of the Tamiami Trail at the SR 60 intersection. It is normally three lanes wide, but between Interstate 4 and the northern terminus of SR 569 is only two lanes wide. The unsigned state highway is 5.6 miles long. At the northern terminus, US 41 turns west. (If one continues straight, 40th Street leads to Busch Gardens Africa.) Major intersections include State Road 574, SR 569, I-4, SR 60, and SR 618.
In Northern Florida, US 41 runs along the DeSoto Trail between Lake City, Florida and High Springs, and again between Williston and Floral City.
In Atlanta, Highway 41 was formerly carried on Spring Street near Five Points, but it has long been re-routed via Northside Drive around the downtown area (It was a major truck route.) The Georgia Dome, Georgia World Congress Center, and Philips Arena are located off Northside Drive. South of Atlanta, Metropolitan Parkway and Tara Boulevard carry the highway, along with its co-signed partner U.S. 19, towards Griffin. North of Atlanta, the stretch of Highway 41 between Atlanta and Marietta was the first four-laned highway in Georgia - when it was completed in 1938. Now, the Northside Parkway and the Cobb Parkway carry Rte-41 through northern Fulton and Cobb counties. This thoroughfare is the home of Cumberland Mall, the Cobb Galleria, and the Six Flags White Water amusement park. Rte-41 also passes through the Georgia cities and towns of Dalton, Griffin, Macon, Perry, Cordele, Tifton, and Valdosta. Valdosta is the last major stop before reaching Florida. The Atlanta Motor Speedway is located on U.S. Highways 19 and 41 in Hampton. Highway 41 has been re-routed in Barnesville and been designated as a truck route and possible industurial area.
U.S. 41, joined by U.S. 76, enters Tennessee east of Interstate 75 on the outskirts of East Ridge. It is called "Ringgold Road" through East Ridge up to the Bachman Tunnel, where it enters Chattanooga. In Chattanooga, U.S. 41/U.S. 76 becomes Westside Drive up to the intersection with Dodds Avenue, where for a short distance it is coexistent with Dodds Avenue. Then U.S. 41/76 becomes East Main Street in downtown Chattanooga up to the intersection with Broad Street (U.S. 11/U.S. 64). At that point U.S. 76 terminates, U.S. 72 begins, and the now-U.S. 41/U.S. 76 merges with U.S. 11/U.S. 64, trekking southwestward around the base of Lookout Mountain into the Tiftonia community. Just west of Tiftonia, U.S. 11 splits off, and it veers southwestward into Georgia. The now-U.S. 41/64/72 takes a westward path from Hamilton County into Marion County.
After crossing the River, U.S. 41 passes John James Audubon State Park, and passes slightly east of the city of Henderson. The route then crosses into Webster County, where it passes through the town of Sebree. Next, it crosses into Hopkins County and passes through Slaughters, Hanson, Madisonville, Earlington, and Nortonville. It then goes into Christian County and Todd County.
For its entire length north of Evansville, U.S. 41 passes through largely rural portions of far western Indiana. It overlaps U.S. Routes 150 and 52 through some of these areas. U.S. 41 is also the main north-south road through Terre Haute, the largest city on U.S. 41 between Evansville and Chicago. However north of Terre Haute, U.S. 41 becomes a secondary road, passing through smaller towns such as Rockville and Attica on the east side of the Wabash River. Indiana State Road 63 is the main route north of Terre Haute in this area since it is a four-lane highway on the west side of the Wabash River.
US 41 enters Illinois cosigned with US 12 and US 20 on Indianapolis Boulevard beneath the Chicago Skyway. At the Illinois–Indiana state line, US 41 enters the Chicago city limits. The three US routes run together for a few miles until US 12 and 20 separate from each other on the far south side. US 41 then runs along numerous small streets to Jackson Park, where US 41 turns north onto Lake Shore Drive, passing through Chicago's lakefront area as it runs along the western shore of Lake Michigan and past downtown Chicago.
On the north side of the city at Lawrence Avenue, US 41 separates from Lake Shore Drive. At Broadway US 41 intersects the eastern terminus of US 14. US 41 continues along local roads in the northern part of the city to Skokie Boulevard, where US 41 turns north and parallels Interstate 94.
In the northern suburbs of Chicago, US 41 joins I-94 north for a short distance before splitting from the expressway and continuing north as the Skokie Highway for roughly to a point near the Wisconsin border. Just south of the border, US 41 rejoins I-94. The two co-signed routes continue northward into Wisconsin.
US 41 is a freeway for nearly 70% of its length through Wisconsin, with exceptions including a stretch in Milwaukee (Lisbon and Appleton avenues) and an expressway section north of Green Bay.
In the U.S. state of Michigan, US 41 is a state trunkline highway that enters the state via the Interstate Bridge between Marinette, Wisconsin and Menominee, Michigan. Along its route, US 41 serves as a major conduit for Michigan traffic. The route from the southern terminus to downtown Houghton is part of the National Highway System. The trunkline comprises mostly two lanes, undivided except for sections that are concurrent with US 2 near Escanaba or M-28 near Marquette. US 41/M-28 is a four-lane expressway along the "Marquette Bypass", and segments of the highway in Delta and Marquette counties have four lanes. and the Copper Country Trail National Scenic Byway. The trunkline ends at a cul-de-sac east of Fort Wilkins State Park in Copper Harbor, serving the Central Upper Peninsula and Copper Country.
Along the route, US 41 passes through farm fields, forest lands, and along the Lake Superior shoreline. The highway is included in the Lake Superior Circle Tour and the Lake Michigan Circle Tour. It also passes through the Hiawatha National Forest and the Keweenaw National Historical Park. Historical landmarks along the trunkline include the Marquette Branch Prison, Peshekee River Bridge and the Quincy Mine.
US 41 initially took a more westerly route between Nashville, Tennessee and Hopkinsville, Kentucky. The current US 41 was U.S. Route 241. In 1930, the two routes became U.S. Route 41W and U.S. Route 41E, but in 1943 the western route became U.S. Route 41 Alternate, with the main US 41 moving to the east route.
In July 2005, efforts started in Congress to re-designate US 41 between Milwaukee, Wisconsin and Green Bay, Wisconsin as Interstate 41. The new Interstate Highway would also include US 45 between current US 41 and the intersection with Interstate 894 and Interstate 94. It is believed that US 41 at that time would then be re-routed to remain concurrent with I-41.