Initially, the Istituto Tecnico Superiore was housed in the Collegio Elvetico on via Senato, currently the seat of the State Archive and for didactic activities it used the technical-scientific collections of other Lombard education and research centres with which it established a symbiotic collaboration: from the Museum of Natural History to the Lombard Institute of Sciences, Letters and Arts, equipped with an impressive wealth of technology, to University of Pavia, to the Botanical Gardens. The most enduring relationships were established with the Società d'Incoraggiamento d'Arti e Mestieri which initially allowed the institution to use its mechanical and chemistry laboratories for lessons and exercises, but in the early 1900's more intense forms of collaboration were promoted, leading to the creation of the Laboratory-School for Electrical Workers (SLEO) frequented by engineering students during the day and by workers in the evening.

A few years after it was founded, Milan's mayor at the time, the commendatory Antonio Beretta, helped the institution find a "more worthy location". The school was transferred to the Palazzo della Canonica building in Piazza Cavour. Palazzo della Canonica, the former home of the Humiliati religious order of Brera, spans along the road currently known as via del Vecchio Politecnico and, up until 1888, it also housed the Literary-Science Academy which shared courses of Italian, business and languages with Politecnico.

In the meantime, the Istituto Tecnico Superiore acquired its own collections of Technical Physics, Geodesy, drawings and models. This increase in endowments was also thanks to the contributions of entrepreneurs from Lombardy and other areas. The first donation in 1871 was made by the cotton industrialist Eugenio Cantoni with the aim of creating a course in Business Administration. In 1886, with the generous contribution of the pharmaceutical entrepreneur Carlo Erba, "a special school of electricity" was created, the Carlo Erba Electrical Institution. In 1893, on the initiative of Cesare Saldini and Giuseppe Ponzio, respective professors of Mechanical Technology and Industrial Mechanics, together with the financial support and equipment donation from a group of industrialists, the first Italian laboratory of applied mechanics was set up, based on the model of the laboratories of the technical schools in America. In 1897 a consortium of leading paper manufacturers was founded, supporting a laboratory for research on paper, subsequently transformed into an experimental station for paper industry and textile fibres. In 1902, in support of the graduate school of chemistry, founded in 1899 and with a significant contribution from the savings banks of the Lombardy provinces, the "Principessa Jolanda" School of Electrochemistry was founded, while in 1908 the school and laboratory for the oil and fat industries was created.

Such growth required additional space, so new laboratories were built on a portion of the adjacent garden of Villa Reale, granted to the school for its use by King Vittorio Emanuele III. With this development, Politecnico came to occupy an area of nearly 10,000 square meters, 6,500 of which were indoors.

In 1913 an agreement was signed between the government, the city and the Milan Chamber of Commerce, with the support of the savings banks of the Lombary Provinces, to decentralise and bring together in one place the institutions of higher learning scattered throughout the city. The choice of the location fell on the suburban area of Cascine Doppie, "in the expanse of meadows in Lambrate", as Gadda said, where in 1927, upon the completion of construction work following the interruption caused by the war, Politecnico was transferred to the complex that continues to be its main headquarters today.

The complex of buildings destined to house the University, designed by Gaetano Moretti and Augusto Brusconi, professors at the University and built by a technical department made up by the engineers Francesco Belloni, Giannino Ferrini and Vittorio Verganti, all Politecnico graduates, consists of six buildings distributed with perfect symmetry and connected by characteristic shelters and large underground connected tunnels, occupies an area of 50,000 square meters. At the top of the building that houses the offices of the Rector and the boardroom is a clock tower that strikes the hours on two bells that originated from Palazzo della Canonica, one of which bears the inscription of the date: 1863.

Large laboratories were set up in the new locations, the fittings and initial operating expenses of which were financed by the Fondazione Politecnica Italiana, an entity formed by industrial companies and banks to "promote the study, teachings and research in all fields of civil, industrial and electrical engineering." Based on the model of the Fondazione Politecnico and with similar purposes the Fondazione Ing. Giorgio Enrico Falck, the Fondazione Gianfranco ed Eugenio Tosi, the Fondazione Ing. Carlo Vanzetti and many others were formed which, from the mid-twenties, contributed to enriching the educational offering with the creation of graduate schools: the first, that in road engineering in 1925, followed by the school of specialization for reinforced concrete construction, that of engineering insurance, one in gas engineering, in agricultural engineering, in metallurgy, electrochemistry, physical chemistry and in iron and steel. In 1934 the School of Architecture was founded by Gaetano Moretti, the faculty's first president. In the same year on the initiative of the "Centre of Studies and Experiences for Flying and Sailing" was created for the design, construction and testing of gliders and powered aircraft, later named "Liberato de Amici", to commemorate one of the student founders who died during the flight tests sailing the seashores in 1935. In 1937 the university officially assumed the name of Regio Politecnico di Milano.

In the years following World War II, there was a rapid increase in enrolments and a development in study programmes: from traditional bachelor's programmes in Civil Engineering (construction, hydraulics and transportation) and Industrial Engineering (mechanical, electrical and chemical) offered along with those in Nuclear Engineering, Electronics, Aeronautics, Soil Protection, as well as a degree course in Economic Organization. These were parallel to the teachings of the School of Architecture, which became more specialised and larger (composition, humanities, urban planning) resulting in an urgent need for more space. The expansion was built towards the eastern and northern side of the quadrangle of the university campus. In addition to the expansion on via Ponzio, buildings were constructed to house the institutes (referred to as Departments since 1982) of Electronics, Aerospace and the "Enrico Fermi" Nuclear Research Centre (CeSNEF). This latter centre, which had to accommodate the nuclear reactor, the first reactor at an Italian university, required a building with a special technical design which was developed by Giovanni Bonicalzi, a professor of architecture. In addition to via Bonardi, designed by a group of architects, including Gio Ponti, the School of Architecture was built, which was later expanded (1982-86) towards via Ampère, with a building designed by Vittoriano Viganò and buildings with the name of Trifoglio (Clover) and Nave (Ship) for the Departments of Mathematics and Mechanics.