I-75 starts at an interchange with SR 924 and SR 826 on the HialeahMiami Lakes border in suburban Miami. After an intersection with the Homestead Extension of Florida's Turnpike and an interchange with I-595 and the Sawgrass Expressway, the Interstate leaves the Miami metropolitan area and turns westward to travel through the Everglades along the tolled Alligator Alley, which brings the highway to the Gulf Coast and Naples, where it again heads north. Passing through Bonita Springs, Fort Myers, and Sarasota, I-75 encounters a series of construction projects that will increase the lane count from two lanes in each direction to three in each direction. The freeway enters the Tampa Bay metropolitan area before the interchange with I-275 northbound, which handles St. Petersburg-bound traffic. Within the Tampa metro are three more major junctions: One with the Lee Roy Selmon Expressway which carries traffic into downtown Tampa; one with I-4 which carries traffic across the center of the state to the East Coast; and another as I-275 traffic defaults back onto northbound. The freeway proceeds to enter suburban portions of Pasco, Hernando, and Sumter counties on its way to Ocala and Gainesville. At Lake City, Florida, the Christopher Columbus Transcontinental Highway, I-10, intersects with I-75, providing routes toward Jacksonville, Florida; Tallahassee, Florida; Pensacola, Florida; Mobile, Alabama; New Orleans, Louisiana; and points westward. Afterward, the northmost stretch of I-75 in Florida exits the Sunshine State into southern Georgia.
The freeway enters Tennessee directly in the Chattanooga metropolitan area, where it intersects with I-24. Exiting Chattanooga to the northeast, I-75 passes through an area known for dense fog. Twelve people were killed and 42 were injured in a 99-vehicle accident on that stretch of I-75 in heavy fog on December 11, 1990. I-75 does not meet any other highways until it overlaps Interstate 40 near Farragut and heads eastbound. Together, they enter the outskirts of Knoxville, where I-75 overlaps itself with a different road, this time I-640, but only for a short time. When the two meet I-275, I-75 encounters some of its highest points of elevation through the Cumberland Mountains and Cumberland Plateau region, cutting through the uppermost peaks and ridges of the mountains.
I-75 continues northbound through the hilly, rugged terrain of the Cumberland Plateau region of Kentucky passing through London and Richmond, eventually reaching Lexington, where it briefly runs concurrently with I-64 before splitting off for Cincinnati, Ohio. Near Walton, I-71 merges with I-75, making for yet another overlapped portion of freeway. I-275, which is the Cincinnati beltway, is then intersected by I-71/I-75. After passing through Covington, the freeway crosses the Ohio River via the lower level of the Brent Spence Bridge (while the southbound direction uses the upper level) and continues into Cincinnati.