One of the six original programmers of ENIAC, the first general-purpose electronic digital computer, Holberton made foundational contributions to the history of computing. During World War II, while the men were fighting, the Army needed women to compute ballistics trajectories. Holberton was hired by the Moore School of Engineering to work as a "computer", and was soon chosen to be one of the six women to program the ENIAC. Classified as "subprofessionals", Holberton, along with Kay McNulty, Marlyn Wescoff, Ruth Lichterman, Betty Jean Jennings, and Fran Bilas, programmed the ENIAC to perform calculations for ballistics trajectories electronically. Their work on ENIAC earned each of them a place in the Women in Technology International Hall of Fame.
After World War II, Holberton worked at Remington Rand and the National Bureau of Standards. She served as Chief of the Programming Research Branch, Applied Mathematics Laboratory at the David Taylor Model Basin in 1959. Holberton helped to develop the UNIVAC, wrote the first generative programming system (SORT/MERGE), and also the first statistical analysis package, which was used for the 1950 US Census.
She worked with John Mauchly to develop the C-10 instruction for BINAC, which is considered to be the prototype of all modern programming languages. Holberton also participated in the development of early standards for the COBOL and Fortran programming languages with Grace Hopper.
