Merrill showed an early interest in natural history, collecting and identifying plants, birds' eggs, rocks, and minerals.

In 1894 he entered the University of Maine with the intention of studying engineering but soon switched to a general science curriculum where he focused on the biology and classification of flowering plants.

[3] In 1899 Merrill accepted a position with the United States Department of Agriculture in Washington D.C. as an assistant to Frank Lamson-Scribner, an authority on the classification of grasses and a pioneer plant pathologist.

[citation needed] At the end of the Spanish–American War, the United States Taft Commission established the Insular Bureau of Agriculture in Manila.

Over the years Merrill's responsibilities continued to grow until he became both the Director of the Bureau of Sciences and a Professor of Botany at the University of the Philippines.

He collected and studied plants not only from the Philippines but also from the greater Asia-Pacific region including Indonesia, Malaysia, Indochina, China, and Guam.

At Berkeley he led a reorganization of the faculty, revised the curriculum, emphasized academic training of staff, added buildings and equipment, and stressed fundamental research.

During his spare time, Merrill continued to work on systematic botany of the Asia-Pacific flora and added more than 100,000 specimens from that region to the university herbarium.

During his short tenure as director Merrill built administrative offices and greenhouses, started a library, established an herbarium of 180,000 specimens and planted 1,200 species in the gardens.

[2][3] In 1929, Merrill accepted dual appointments as Director of the New York Botanic Garden and Professor of Botany at Columbia University.

Up to 300 personnel were employed building walks, roads, fences and other infrastructure in the gardens; or they worked in the herbarium as mounters, artists, secretaries, librarians, clerks and technicians.

Once the substantial backlog of unmounted material was complete, specimens were mounted for other institutions including the Arnold Arboretum and the Gray Herbarium.

In 1931 Merrill established a new journal focused on systematic botany and plant geography, named Brittonia after Nathaniel Lord Britton, a co-founder of the Garden.

Meanwhile, Merrill continued to publish numerous papers on Asia flora as well as articles dealing with the cultivation and dispersion of domesticated plants.