During Cardinal Borromeo's sojourns in Rome, 1585–95 and 1597–1601, he envisioned developing this library in Milan as one open to scholars and that would serve as a bulwark of Catholic scholarship against the treatises issuing from Protestant presses. To house the cardinal's 15,000 manuscripts and twice that many printed books, Construction began in 1603 under designs and direction of Lelio Buzzi and Francesco Maria Richini. When its first reading room, the Sala Fredericiana, opened to the public, December 8, 1609, it was, after the Bodleian Library in Oxford, the second public library in Europe. One innovation was that its books were housed in cases ranged along the walls, rather than chained to reading tables, a practice seen still today in the Laurentian Library of Florence. A printing press was attached to the library, and a school for instruction in the classical languages.
Constant acquisitions, soon augmented by bequests, required enlargement of the space. Borromeo intended an academy (which opened in 1625) and a collection of pictures, for which a new building was initiated in 1611–18 to house the Cardinal's paintings and drawings, the nucleus of the Pinacoteca.
Cardinal Borromeo gave his collection of paintings and drawings to the library too. Shortly after the cardinal's death his library acquired twelve manuscripts of Leonardo da Vinci, including the Codex Atlanticus. There are now some 12,000 drawings by European artists, from the 14th through the 19th centuries, which have come from the collections of a wide range of patrons and artists, academicians, collectors, art dealers, and architects. Prized manuscripts, including the Leonardo codices, were requisitioned by the French during the Napoleonic occupation, and only partly returned after 1815. On 15 October 1816 the Romantic poet Lord Byron visited the library. He was delighted by the letters between Lucrezia Borgia and Pietro Bembo ("The prettiest love letters in the world") and claimed to have managed to steal a lock of her hair ("the prettiest and fairest imaginable.") held on display.
The Library has a college of Doctors, similar to the scriptors of the Vatican Library. Among prominent figures have been Giuseppe Ripamonti, Ludovico Antonio Muratori, Giuseppe Antonio Sassi, Cardinal Angelo Mai and, at the beginning of the 20th century, Antonio Maria Ceriani, Achille Ratti, the future Pope Pius XI, and Giovanni Mercati.