The Department of Invertebrate Zoology at the Museum of Comparative Zoology houses some of the most extensive and historically important metazoan and protozoan collections available to researchers today. There are an estimated 307,100 lots of approximately one million specimens in the collections, including the primary types for more than 7,663 nominal species, plus several thousand paratypes. The collections of the Department of Invertebrate Zoology contain all the invertebrates excluding molluscs, insects, deuterostomes, and the "lophophorates". The spider collection is the second largest in the world; the crustacean collection is one of the largest in the U.S.; the cnidarian holdings are among the ten finest in the world; and the collection of hexactinellid sponges is probably the best in the world. The myriapod collection is also of great importance given the large number of deposited types.

The collections contain specimens from diverse geographical regions of the World, and from both terrestrial and aquatic habitats. Many of the terrestrial and freshwater specimens were collected during the 19th century Thayer Expedition to Brazil , the "Hassler" Expedition around the coast of South America, and the U.S. Geological Surveys of the Territories; in the 1930's, A. Loveridge and J. Griswold made extensive collections in Africa and Asia, respectively. Marine material also includes specimens collected by numerous other historic expeditions, including the 19th century U.S. Coast Surveys (e.g., the "Bibb" and "Blake" expeditions), the "Challenger" and "Albatross" cruises, and the "Atlantis" Harvard-Havana 1938-1939 Expedition to the Caribbean. More recent acquisitions of marine material include North Atlantic specimens from various National Marine Fisheries Service cruises, the reference collection for the Massachusetts Water Resource Association Boston Harbor clean-up, and the Howard Sanders deep-sea collections from the Woods Hole Oceanographic Institution. Other unique material housed by the department includes a collection of fossil Acari in Baltic amber, Petrunkevitch spider type specimens in amber, and Scudder spider type specimens from the Oligocene Florissant lake beds in Colorado.

A long history of arachnid collection and curation has resulted in one of the world's largest spider collections, with extensive and historically important collections made by many of the major North American arachnologists.