The southernmost institution of the “Great 28” in the Florida College System, The College of the Florida Keys was established in 1965 as “Monroe County Junior College.” The first classes were held at the former Douglass High School in downtown Key West. In 1968, the name was changed to “Florida Keys Junior College” upon the opening of the main campus on Stock Island, and in 1970, the name was changed again to "Florida Keys Community College."

The College experienced several key developments in its early years. The first 20 years brought programs such as diving, business, and emergency medical services as well as the opening of the Upper Keys Center in Tavernier in 1980 and the Middle Keys Center in Marathon in 1982.

In the 1990s, the Key West Campus expanded its facilities to include the Charlie Toppino Welding Technology Lab, the Ron Saunders Student Center, the Public Safety Building, and a scuba diving complex. In 1997, the College unveiled a new $40 million campus named after Dr. William A. Seeker, the College president who championed its funding.

In fall 2011, the College opened a 100–bed waterfront residence hall, Lagoon Landing, making it easier for students from outside of the Keys to relocate to study at the College.

The College’s leadership history reflects a succession of presidents who shaped the College’s progress. Under the leadership of the first president Dr. Merrill A. Symonds, the College opened its doors and expanded access to higher education and training opportunities to Monroe County residents. Dr. John Sylvester Smith served as president from 1967 to 1979. Dr. William Seeker, the third president, served from 1979 until his retirement in 2007. He was bestowed the honor of “President Emeritus” by the District Board of Trustees. Dr. Jill Landesberg–Boyle then took the helm as the College’s first female president in 2007 and held the position through 2009. The College then welcomed its fifth president Dr. Lawrence W. Tyree, who was also named “President Emeritus” upon his retirement in 2012.

In 2012, Dr. Jonathan Gueverra became the sixth president and CEO of the College. In his inaugural address, he laid out his vision of building bridges between the College’s past achievements and future efforts to meet the diverse educational needs of all constituents. Under Dr. Gueverra’s leadership, the College has renewed and strengthened relationships with valuable partners, organizations, and the community at large.

With support from the largest Keys industry, the College launched a Hospitality and Tourism Management initiative in 2013. Opportunities expanded in 2016 to include two associate degrees, in Hospitality and Ecotourism and Culinary Management, as well as seven certificates.

In 2014, the College opened a new Marine Technology Building on the Key West Campus. Adjacent to the dive training lagoon, the facility provides an enhanced learning environment, particularly for the College’s signature Marine Engineering, Management and Seamanship program.

The College launched its first bachelor’s degree in January 2017. The highly–anticipated Bachelor of Applied Science in Supervision and Management (BAS–SM) provides much needed access to public baccalaureate education to the local population while attracting more students from across the nation to study in the College’s small and engaging learning community in paradise. The BAS–SM provides two concentration options: hospitality or management. The College has continued to increase its baccalaureate options by adding a Bachelor of Science in Nursing in fall 2019, a Bachelor of Science in Marine Resource Management in fall 2020, and a Bachelor of Science in Exceptional Student Education in 2023.

In 2019, the College changed its name from Florida Keys Community College to The College of the Florida Keys to reflect its baccalaureate granting status. The College continued its brand evolution with the introduction of a new mascot in 2021. The Tuga, an abbreviation of “tortuga,” the Spanish word for turtle, is a fictional sea turtle with an Ocean Blue body with lateral lightning bolts and a Sunset Orange shell. Along with the new mascot, the College relaunched sports after a 45-year hiatus with men’s and women’s swim teams.

Also in 2021, the College opened a new Upper Keys Center in Key Largo. The two-story center allows the College to significantly improve and expand its service to the community in northern Monroe County with bachelor’s and associate degrees, workforce training and testing, and community enrichment activities.

In 2023, CFK expanded opportunities to younger students and their families with the opening of the CFK Academy on the Key West Campus. The tuition-free public charter high school, focuses on science, technology, engineering, and math (STEM) and Career Technical Education (CTE) and encourages academic acceleration through Dual Enrollment.