Interstate 75 (I-75) is a part of the Interstate Highway System and runs from Hialeah, Florida, a few miles northwest of Miami to Sault Ste. Marie in the Upper Peninsula of Michigan. I-75 begins its national northward journey in Hialeah, running along the western parts of South Florida before traveling westward across Alligator Alley, resuming its northward direction in Naples, running along Florida's Gulf Coast, passing the cities of Ft. Myers, Port Charlotte, and the Tampa Bay Area, before turning inward towards Ocala, Gainsville and Lake City before leaving the state and entering Georgia. I-75 runs for 471 miles (758 km) in Florida, making it the longest interstate in any state east of the Mississippi River. The interstate maintains a speed limit of 70 mph (110 km/h) for its entire length in Florida.

The portion of I-75 from Tampa northward was a part of the original 1955 Interstate Highway plans, with I-75's southern terminus at I-4's current western terminus. The interstate was extended south to Miami was established in 1968 after massive growth in Southwest Florida, which resulted in I-75 being realigned to travel on the eastern fringes of the Tampa Bay area, and the last portions of the highway was opened in 1993.

For FDOT inventory purposes, it is designated as SR 93 for most of its length in Florida (with exception to the Tampa Bay area, where SR 93 follows I-275, while SR 93A travels with I-75 in the latter's bypass of the area).

Interstate 75 begins its northward journey at SR 826 (Palmetto Expressway) and SR 924 (Gratigny Parkway) in Hialeah, near Miami.

Leaving Hialeah, I-75 serves some of the western fringes of South Florida as an eight lane highway. After an exit with SR 860, I-75 has a southbound interchange with the Homestead Extension of Florida's Turnpike before crossing into Broward County. There, it continues through the western suburbs of Pembroke Pines, Weston, Miramar, Davie, and Southwest Ranches. At the junction of SR 869 (Sawgrass Expressway) and I-595, I-75 (while maintaining its north/south status) enters an east/west trajectory as it crosses the Everglades by way of Alligator Alley, a toll road which was constructed originally as a two-lane highway before it was converted to a four-lane highway meeting Interstate Highway standards. At this point, I-75 loses a lane in each direction, heading west, losing another lane west of the US 27 interchange, the last interchange before the toll plaza. The Alligator Alley section west of Fort Lauderdale, Florida and east of Naples is due east/west and is one of only two sections of I-75 that are tolled (the other is the Mackinac Bridge). Just west of the Snake Road exit (exit 49), Alligator Alley crosses into Collier County and the Big Cypress National Preserve. Once near Naples at Collier County Road 951 (Exit 101), Interstate 75 makes a sharp turn and resumes its north-south trajectory. Interstate 75 runs parallel with the southwest coast of Florida and passes near Bonita Springs, Fort Myers, Punta Gorda, Port Charlotte, Sarasota and Bradenton before reaching the Tampa Bay Area metropolis consisting of Tampa and St. Petersburg.

In Ellenton I-275, splits from I-75 to serve St. Petersburg and Pinellas County via the Sunshine Skyway Bridge and Tampa via the Howard Frankland Bridge. I-75 parallels the eastern shore of Tampa Bay as a bypass route of the Tampa Bay Area, as it passes by the communities of Brandon, Temple Terrace and New Tampa. Two expressways access downtown Tampa from I-75: the Lee Roy Selmon Expressway (SR 618) and I-4. Within the Tampa Bay Metropolitan Area, many interchanges are far more complex than mere diamond, cloverleaf, or even SPUI interchanges. Aside from the large turbine interchange with I-4 (Exit 261), there are interchanges with Fowler Avenue (Exit 265) and Fletcher Avenue/Morris Bridge Road (Exit 266) that contain both loops and flyovers. A flyover ramp was built from southbound Bruce B. Downs Boulevard (Exit 270) to southbound I-75.

At the Hillsborough-Pasco county line (south of SR 56 (Exit 275)), I-275 rejoins I-75 (at Exit 274, southbound only) and I-75 changes into a northeast-southwest trajectory as it passes through Pasco, Hernando and Sumter Counties where it runs through parts of the Withlacoochee State Forest on its way to the junction with Florida's Turnpike. Widened median segments exist in Northern Pasco County, Hernando County, and in Sumter County north of County Road 476-B (Exit 309). Some of these median segments are actually considered part of the Withlacoochee State Forest itself. The Withlacoochee State Trail runs beneath I-75 between US 98/SR 50 (Exit 301) and the Hernando-Sumter County line, where it also crosses over the Withlacoochee River.

After Florida's Turnpike (accessible from southbound Interstate 75 only), Interstate 75 changes into a general northwest-southeast trajectory, which is sustained to the Georgia state line and beyond. Interstate 75 passes beneath the Cross Florida Greenway, which contains a land bridge built across the highway in 2001 between Exits 341 and 350, before entering the City of Ocala, and passing by the cities of Gainesville and Lake City and crosses I-10 at an interchange before entering the state of Georgia, near Valdosta.

Interstate 75 runs closest to U.S. 41 except between Tampa and High Springs. It runs closer to U.S. 301 between Ellenton and Temple Terrace, and again from Dade City to Sparr. From Belleview to Lake City it runs closest to U.S. 441.

Originally, I-75 was to be built to Tampa, terminating at I-4's current western terminus, and was completed in 1969. In the mid-1960s, Florida's state government proposed to build a toll road from the Tampa Bay area to Ft. Lauderdale through Alligator Alley. Those plans were cancelled in 1968, when it was announced that I-75 would be extended to Naples and eventually South Florida. After I-75's route was extended to connect into the Miami area, a Tampa Bay bypass was built east, signed as I-75E, with the original route, now extending to St. Petersburg and becoming a loop, signed as I-75W. After the AASHTO phased out route suffixes on Interstates, I-75E became I-75, and I-75W was renamed I-275.

From Naples, Interstate 75 was originally intended to run along the current route of US 41/Tamiami Trail, and connecting to I-95 along the current route of State Road 836/Dolphin Expressway. Due to environmental concerns of the Tamiami Trail and wanting to upgrade the then dangerous Alligator Alley, the latter was upgraded to interstate standards. After rerouting I-75 south of what would be I-595, I-75 was to terminate at I-95 in North Miami, but due to local opposition, I-75 was not built past its current terminus of the Palmetto Expressway. The last section to be signed was Alligator Alley in 1993.

On January 28, 2002, the Florida Department of Transportation began a transition of interchange numbers from sequential exits to mileage-based exits.

In October 2009, the Florida Department of Transportation began a relocation project for the northbound ramp of Exit 275, which includes a connecting ramp with Interstate 275. This project will prevent weaving in the vicinity of I-275 and SR 56, a hazard that has occurred since the Exit 275 and SR 56 were built across I-75 in 2003. Completion is expected to occur in the Spring of 2012.

Plans are under way to redesign the interchanges with the north end of Florida's Turnpike (Exit 328) and SR 44 (Exit 329), connecting them with collective-distributor roads, and eliminating left-hand access to Florida's Turnpike from the main southbound lane. This is a joint effort between the Florida's Turnpike Enterprise and Florida Department of Transportation and is planned to occur in 2016.

Along Interstate 75 are 9 pairs of rest areas along the length of the freeway. In addition, there are separate facilities for each direction of I-75 in Hamilton (southbound) and Suwannee (northbound) Counties and a welcome center south of the state line. Exits 131 and 161 each have a single facility accessible from both travel directions on I-75, as well as the intersecting highway. Each rest area has rest rooms, vending machines, picnic tables, dog walk areas and nighttime security. The welcome center also has travel information and free orange juice.

Motorist-aid call boxes are located on both outside shoulders of the road every mile (1.6 km), and send a signal indicating the need for gasoline, repair (tire or engine), or emergency services (police, ambulance, or firefighters). Call boxes can also be found at some rest areas.