Fortune smiled on the single mother when she was offered employment as a maid in the home of Professor Edward Charles Pickering, the director of the Harvard Observatory. Pickering, a brilliant but driven man, who was also a vissionary became frustrated with his male employees at the Observatory and famously declared his maid could do a better job. This proved to be a prophetic statement.
In 1881, Pickering hired Fleming to do clerical work and some mathematical calculations at the observatory. While there, she demonstrated her intelligence and proved Pickering's declaration by devising and helping implement a system of assigning stars a letter according to how much hydrogen could be observed in their spectra, a distinctive pattern produced by each star when its light is passed through a prism. Stars classified as A had the most hydrogen, B the next most, and so on. With this system, later to be named in her honor, she successfully cataloged over 10,000 stars within the next nine years. (Annie Jump Cannon improved upon this work to develop a simpler classification system based on temperature.) This work was published in 1890 in a book titled Draper Catalogue of Stellar Spectra.
Her duties were expanded and she was placed in charge of dozens of young women hired to do mathematical computationss, known as "compuiters," who performed work which would today be performed by electronic computers. She also edited the observatory's publications. In 1899, Fleming was given the title of Curator of Astronomical Photographs, the first such appointment given to a woman.. In 1906, she was made an honorary member of the Royal Astronomical Society of London, the first American woman to be so elected.
In 1907 she published a study of 222 variable stars she had discovered. Soon after, she was appointed honorary fellow in astronomy of Wellesley College. Shortly before her death, the Astronomical Society of Mexico awarded her the Guadalupe Almendaro medal for her discovery of new stars. During her work, she discovered 59 gaseous nebulae, over 310 variable stars, and 10 novae. In 1910 she published her discovery of "white dwarfs."
She died in Boston of pneumonia on May 21, 1911.