Mieli is now considered one of the founders of the discipline of the history of science, as one of the first to consider it a discipline it its own right.
His history of science career began whilst a chemistry lecturer in Rome, building on interest stimulated in his studies in Germany.
In 1912, he founded, and briefly maintained, a section in the journal Rivista di filosofia for the history of science. He edited the Italian bibliography for the then new journal Isis, and in 1916, published a pamphlet calling for a chair of history of science to be created in Italian universities. He also wrote several books on history of science topics, and edited a series on classic texts in science and philosophy for Laterza, an Italian publisher.
He taught history of science at the University of Rome between 1919 and 1928, and the University of Perugia in 1926. He was elected a member of Deutsche Akademie der Naturforscher Leopoldina in 1925.
In 1919, he founded the journal Archeion (later renamed Archives internationales dhistoire des sciences' and still published), which he continued to edit until three years before he died. Many organisations, including UNESCO, provided funding for the journal, which he also subsidised from his own finances.
In 1928 he moved to Paris. There, Mieli co-founded, and served as permanent secretary of the Comite International dHistoire des Sciences (the International Committee for the History of Science), renamed the International Academy of the History of Science at its First International Congress of the History of Science, held in Paris in May 1929. At that meeting, Archeion' became the official journal of the Academy.
That same year, Mieli was invited to create and direct a Unit for the History of Science at the Centre international de synthèse, which had been created in 1925 by Henri Berr. The Unit officially opened on 22 January 1930. He worked there, collaborating with Helene Metzger until 1939, when he moved to Argentina. He was very ill when he arrived in Argentina, and spent several months in hospital.
He worked at the Universidad Nacional del Litoral in Santa Fé, from 1940 to 1943 where he founded an Institute for the History and Philosophy of Science and continued to edit Archeion. Following the 1943 Argentine coup détat and the new Governments intervention in the university, his employment contract was cancelled, and he retired to Florida, near Buenos Aires.
In poor health, and without the financial backing of the university, he ceased being editor of Archeion, which was subsequently relaunched as Archives internationales dhistoire des sciences. He began to write Panorama general de historia de la ciencia,' a survey of the history of science, intended to be an eight-volume set. He completed and published the first two volumes, and had proofs of the third, fourth and fifth, by the time he died.