Mary E. (Mary Emma) Byrd was born on November 15, 1849 in Le Roy, Michigan to Rev. John Huntington Byrd and Elizabeth Adelaide Lowe Byrd. When Mary was six years old, her family moved to Leavenworth, Kansas, and her father, a firm abolitionist, managed a station of the Underground Railroad. Byrd graduated from Leavenworth High School before attending Oberlin College from 1871-74. She left Oberlin before graduating, and the following year began attending the University of Michigan, where she received a B.A. in 1878. In 1879 Byrd worked as the principal of Wabash High School in Indiana until 1882, when she left to study astronomy at Harvard College Observatory under Dr. E.C. Pickering. In 1883 she became the First Assistant at the Godsell Observatory at Carleton College in Minnesota. In 1887 she was appointed Director of the Smith College Observatory and professor of astronomy. In 1899 she published her first book, . Carleton College awarded Byrd an honorary Ph.D. in astronomy in 1904.

In 1906, Byrd resigned from her positions at Smith over philosophical differences about accepting money from Andrew Carnegie and John D. Rockefeller. Upon her resignation, she returned to Lawrence, Kansas, and in 1913 published her second textbook, . She continued writing, and contributed many articles to magazine. Byrd was a member of the Astronomical and Astrophysical Society of America, Astronomical Society of the Pacific, and the British Astronomical Association, as well as the Anti-Imperialist League of Northampton.

In 1932 Byrd was stricken with cerebral hemorrhage, of which she died two years later at her home on July 13, 1934.