Monroe County is the southernmost county of the state of Florida. As of the 2020 census, the population was 82,874. Its county seat is Key West. Monroe County includes the islands of the Florida Keys and comprises the Key West-Key Largo Micropolitan Statistical Area. Over 99.9% of the county's population lives on the Florida Keys. The mainland, which is part of the Everglades, comprises 87% of the county's land area and is virtually uninhabited with only 17 people recorded in the 2020 census.

Monroe County was created in 1823. It was named for James Monroe, the fifth president of the United States from 1817 to 1825.

According to the U.S. Census Bureau, the county has a total area of 3,738 square miles (9,680 km²), of which 983 square miles (2,550 km²) (26.3%) is land and 2,754 square miles (7,130 km²) (73.7%) is water. It is the largest county in Florida by total area.

More than 99.9 percent of the Monroe County population lives in the island chain known as the Florida Keys.

Two thirds of the large area in what local residents call "mainland Monroe" is uninhabited by virtue of being part of the Everglades National Park, and the remainder by the Big Cypress National Preserve in the northeastern interior. The area, officially named Cape Sable Census County Division, is virtually uninhabited. This area has 87.4 percent of the county's land area (859.6 out of 983 sq mi (2,546 km²)), but it had only 0.022 percent of the county's population (18 out of 82,170) as of the 2021 American Community Survey. The Census Bureau defines this area as Census Tract 9800 of Monroe County, Florida.

In mainland Monroe, the only three populated places appearing on detailed maps and in the USGS geographic name database are Flamingo, Pinecrest, (not to be confused with much larger Pinecrest of neighboring Miami-Dade County), and Trail City. Flamingo, on the south coast and at the end of State Road 9336 (Flamingo Lodge Highway), is the location of the Flamingo Lodge and the Flamingo Ranger Station (with Visitor Center & Marina). 7 mi (11 km) northeast on the highway is the West Lake Trail (station). Pinecrest, located in the northern interior of the county (in the Big Cypress National Preserve) on Loop Road (given that name since it forms a loop with U.S. Highway 41 further north), hosts the Loop Road Education Center. Trail City is 4 mi (6 km) west of Pinecrest on Loop Road. Loop Road can be found on most maps as CR 94, although the roadway no longer has a numbered designation and is now managed by the National Park Service.

Between the south coast of Florida's mainland and the Florida Keys is Florida Bay, which is encompassed by the Everglades National Park and contains numerous islets or keys.

The county is coterminous with the Key West-Key Largo, Florida Micropolitan Statistical Area (μSA), with Key Largo and Key West designated as principal cities. The μSA was first defined in 2003 as the Key West-Marathon, Florida Micropolitan Statistical Area. The name was changed to Key West, Florida Micropolitan Statistical Area in 2006, and to Key West-Key Largo, Florida Micropolitan Statistical Area in 2023. The μSA is part of the Miami-Port Saint Lucie-Fort Lauderdale Combined Statistical Area.