Mary Flagler, beneficiary of part of the Standard Oil fortune, and her husband Melbert Cary sought respite from New York City at their Millbrook country home. What began as a single estate grew into over 778 hectares (1,924 aces) as the couple purchased 14 farms and properties surrounding the Cannoo Hills west of the village. They built a cottage, named the Tea House, atop one of the two hills and let nature take its course. The surrounding fields and pastures became a refuge for local wildlife. After Mr. Cary died in 1941, Mrs. Cary tended to the property, taking a special interest in the maple trees.

Following her death in 1967, Mary Flagler Cary left her Millbrook estate to a trust. The Mary Flagler Cary Charitable Trust was formed to ensure the maintenance and preservation of her property and to foster "...scientific, ...educational purposes," by a charitable organization "...engaged in the conservation, maintenance, and preservation of natural resources...". In 1971, The New York Botanical Garden was named the custodian of the property. The NYBG developed an arboretum on the site, and over the next decade, the Mary Flagler Cary Charitable Trust funded the development of infrastructure and the hiring of employees to support the new arboretum.

In 1978, the progress and direction of the Mary Flagler Cary Arboretum was assessed by a committee of distinguished scientists. They immediately recognized the unique opportunity provided by the resources of the Mary Flagler Cary Charitable Trust, the Arboretum's 778 hectares of protected land, and the newly developed facilities. The committee recommended the continued integration of academic research, education, and public information. Ultimately, the reviewers suggested the creation of a center for ecological research and education.

The New York Botanical Garden began an international search for an eminent scientist who would realize the potential of the Arboretum's site and resources. In 1983, Dr. Gene E. Likens was named vice president of The New York Botanical Garden and director of both the Arboretum and the proposed ecology center. In September 1983, Dr. Likens founded the Institute of Ecosystem Studies.

Initially a division of The New York Botanical Garden, the Institute became an independent not-for-profit in 1993. Over the past twenty-four years, IES has gained international recognition as a leader in ecological studies, boasting state-of-the-art laboratories, a scientific staff of more than 15 Ph.D. scientists, and an influential publication record.

The site boasts dormitories, residences, a library, an analytical laboratory, and an auditorium. A weekly seminar series, a bi-annual conference series, and periodic workshops help infuse the community with new ideas and dialogue from around the globe. Early affiliations with Cornell University, Rutgers University, the University of Connecticut and Yale University, forged to train graduate students, now reach other universities.

After serving as president and director for twenty-four years, Dr. Likens stepped aside in 2007. The organization's current president, Dr. William H. Schlesinger, came on board in May of 2007. He brings with him expertise in global change ecology and a strong commitment to connecting IES research with policy makers, land managers, educators, and the interested public.