Mellink received her undergraduate training at the University of Amsterdam and her doctorate from Utrecht in 1943. Professor Mellink moved to Bryn Mawr College in the 1946 as a Marion Reilly Fellow and spent the summer of 1947 at the University of Chicago on a Ryerson Grant. During this time she began excavating with Hetty Goldman at Tarsus, in southern Turkey. She began teaching in the Bryn Mawr's Department of Classical and Near Eastern Archaeology in 1949 and retired in 1988; in 1972 she was appointed to the Leslie Clark Chair in the Humanities.From 1950 until 1965 she was involved in the excavations at Gordium, Turkey, together with Rodney Young of the University of Pennsylvania. Mellink's most well-known work focused on the site of Karatas-Semayük in the Elmali plain in Lycia where she explored Early Bronze Age remains and tombs.
Mellink was professor emerita of Classical and Near Eastern Archaeology at Bryn Mawr College. In 1994 she received the Lucy Wharton Drexel Medal for achievement in archaeology from the University of Pennsylvania. She received the Archaeological Institute of America's Gold Medal for Distinguished Archaeological Achievement in 1991. The Ministry of Culture of Turkey recognized her as the Senior American Excavator in 1984 and the Senior Foreign Archaeologist in 1985. In 2001 the Archaeological Institute of America established in her honor the Machteld Mellink Lecture in Near Eastern Archaeology. Bryn Mawr College awarded her the Lindback Foundation Award for Distinguished Teaching in 1975.
She was a Member of the American Philosophical Society, a Fellow of the American Academy of Arts and Sciences, a Research Associate of the University of Pennsylvania Museum, and a Corresponding Member of the Turkish Institute of History, the Royal Dutch Academy of Sciences, the German Archaeological Institute, and the Austrian Archaeological Institute, and many other international archaeological societies.
Her professional service included being President of the American Research Institute in Turkey from 1988-91, President of the Archaeological Institute of America from 1980-84, Trustee of the American Society of Oriental Research, Chair of the Department of Classical and Near Eastern Archaeology at Bryn Mawr College from 1955-83, and Acting Dean of the Graduate School of Arts and Sciences at Bryn Mawr College from 1979-80.