This nature reserve was founded on January 2, 1980, by the Puerto Rico Planning Board (Junta de Planificación) as recommended by the Puerto Rico Department of Natural and Environmental Resources (Departamento de Recursos Naturales y Ambientales de Puerto Rico, DRNA) with the purpose of preserving the subtropical dry forest ecosystems found within these islands, some important sea turtle nesting sites, and the marine habitats found on their surrounding reefs and waters.

[2] Although the island was never permanently populated, throughout its history it has served as a pirate hideout, a place for clandestine meetings for the island's Freemasons during the Spanish Catholic rule, and for secret gatherings of Puerto Rico independence movement leaders such as Ramón Emeterio Betances and Segundo Ruiz Belvis.

[1] The nature reserve covers a land area of approximately 400 acres (412 cuerdas) and it includes the following islands and keys connected by shallow water banks:[1] The islands belonging to the Caja de Muertos Nature Reserve are part of a larger archipelago that extends off Puerto Rico's Caribbean coast from east to west.

Due to the close proximity of Caja de Muertos and Berbería to land, most of the local species originate in the main island of Puerto Rico.

Examples of rare or unique flora species found in the area include serpentine manjack (Varronia bellonis) and Portulaca caulerpoides, which are endemic to Puerto Rico.

It is locally known as higo chumbo, meaning "weighed-down prickly pear" due to the leaning cactus arms caused by the weight of their fruit.

Most of the coral is found on the northeastern reefs along Caja de Muertos; it serves as home and nursery to numerous fish species.