In the 2020 redistricting cycle, the district was drawn as a successor to the previous 18th district and contains all of St. Lucie County and Martin County as well as the northeastern part of Palm Beach County, and includes Port St. Lucie, Fort Pierce, Stuart, Jupiter, and Palm Beach Gardens, as well as Treasure Coast International Airport.

From 2003 to 2013, the 21st district was located in Miami-Dade County and included many of Miami's western suburbs, such as Hialeah, Olympia Heights and Cutler Bay.

In the process, it absorbed the part of Broward County that had previously been in the neighboring 22nd district, which had been renumbered the 21st.

This came after the state supreme court urged the creation of one district covering most of Palm Beach County and another covering most of Broward County and a part of Palm Beach.

As a result of 2015's statewide redistricting, Deutch effectively swapped seats with Lois Frankel, the 22nd District's current representative.