The first building to occupy the site of Goldwin Smith Hall was a wooden structure housing the chemical, agricultural, and photographic laboratories. The north wing of the current building was built in 1893, as a dairy husbandry building, paid for by New York's legislature, the first such funding from the state.

Vladimir Nabokov, author of Lolita, made his office on Goldwin Smith's third floor in the 1950s. Authors Thomas Pynchon, Richard Price, and Toni Morrison attended English classes here. In the basement, researchers in Cornell's world-famous dendrochronology lab divine the age of archaeological artifacts by counting the tree rings in wood samples found at digs.