He was born in New York City in 1855. His father, Clinton Levi Merriam, was a U.S. congressman. He studied biology and anatomy at Yale University and went on to obtain an M.D. from the School of Physicians and Surgeons at Columbia University in 1879.
In 1886, he became the first chief of the Division of Economic Ornithology and Mammalogy of the United States Department of Agriculture, predecessor to the National Wildlife Research Center and the United States Fish and Wildlife Service. He was one of the original founders of the National Geographic Society in 1888. He developed the "life zones" concept to classify biomes found in North America. In mammalogy, he is known as an excessive splitter, proposing, for example, tens of different species of North American brown bears in several genera.
Some species of animals that bear his name are Merriam's Wild Turkey Meliagris gallopavo meriami, the now extinct Merriam's Elk Cervus elaphus merriami, and Merriam's Chipmunk Tamias merriami. Much of his detail-oriented taxonomy continues to be influential within mammalogical and ornithological circles.
Later in life, funded by the Harriman family, Merriam's focus shifted to studying and assisting the Native American tribes in the western United States. His contributions on the myths of central California and on ethnogeography were particularly noteworthy.
His sister Florence Augusta Merriam Bailey was a pioneering ornithologist who introduced the idea of popular field guides for bird identification.