The Department of Chemistry at NCSU goes back to the founding of the North Carolina College of Agricultural and Mechanic Arts in 1889. W. A. Withers was Professor of Pure and Agricultural Chemistry, one of only five original faculty members at the college. The chemistry curriculum was initially listed as engineering courses, although not considered chemical engineering. In 1911 the department moved from Holladay Hall to Winston Hall, where it had use of two classrooms, three teaching labs, and a research lab as well as a prep room, a dark room, and a chemical library. In 1923, chemistry was moved into the School of Science and Business. In 1931 the Consolidated University of North Carolina was established, and the college could no longer grant degrees in pure chemistry. The department was transferred to the School of Agriculture in 1937 and, named the Department of Agricultural and Biological Chemistry, moved to Withers Hall in 1940.

In their 5 November 1957 proposal for the formation of a reconstituted Department of Chemistry, separate from the applied chemistry divisions, Lodwick C. Hartley (Dept. of English), Preston W. Edsall (Dept. of History and Political Science), Clark Lee Allen (Dept. of Economics), and R. R. Hentz (Department of Chemistry) emphasized the importance of instruction in pure chemistry, for which there was, at that time, no dedicated degree program. Their objective was to develop and implement a program of undergraduate instruction in inorganic, analytical, organic, physical, and biological chemistry leading to a bachelors of science degree in chemistry, as well as graduate and research programs leading to masters of science and Ph.D. degrees in all areas from agricultural and biological chemistry to nuclear chemistry. They focused particularly on faculty recruitment and on equipment and facilities.

The "new" Department of Chemistry was moved into the newly organized School of Physical Science and Applied Mathematics in 1959-60. At that time, only 2% of students enrolled in chemistry courses were chemistry majors, leading acting department head W. A. Reid to dub the undergraduate program a "service program to all the curricula on the campus with the exception of the School of Design." In 1965, construction commenced on a new chemistry building, Dabney Hall, doubling research capacity. The building was complete in June 1969. By 2004, the department was large enough to require a new undergraduate lab facility, located in the Fox Science Teaching Laboratory. In 2007, the department numbered 40 full-time faculty, 120 graduate students, and 350 undergrads.