There are few remains of the ancient Roman colony that later became a capital of the Western Roman Empire. During the second half of the 4th century CE, Saint Ambrose, as bishop of Milan, had a strong influence on the layout of the city, redesigning the centre (although the cathedral and baptistery built at this time are now lost) and building the great basilicas at the city gates: Sant'Ambrogio, San Nazaro in Brolos, San Simpliciano and Sant'Eustorgio, which still stand, refurbished over the centuries, as some of the finest and most important churches in Milan. The largest and most important example of Gothic architecture in Italy, the Milan Cathedral, is the fourth largest cathedral in the world after St. Peter's Basilica in Rome, the Cathedral of Seville and a new cathedral in the Ivory Coast. Built between 1386 and 1577, it hosts the world's largest collection of marble statues with the widely visible golden Madonna statue on top of the spire, nicknamed by the people of Milan as Madunina (the little Madonna), that became one of the symbols of the city.

During the rule of the Sforza family, between the 14th and 15th centuries, the old Visconti fortress was enlarged and embellished to became the Castello Sforzesco: the seat of an elegant Renaissance court surrounded by a walled hunting park stocked with game captured around the Seprio and Lake Como. Notable architects involved in the project included the Florentine Filarete, who was commissioned to build the high central entrance tower, and the military specialist Bartolomeo Gadio.

The political alliance between Francesco Sforza and the Florence of Cosimo de' Medici bore architectural fruit, as Milanese building came under the influence of Brunelleschian models of Renaissance architecture. The first notable buildings to show this Tuscan influence were a palazzo built to house the Medici Bank (of which only the main entrance survives) and the centrally planned Portinari Chapel, attached to San Lorenzo and built for the first manager of the bank's Milan branch. Filarete, while in Milan, was responsible for the great public hospital known as the Ospedale Maggiore, and also for an influential Treatise on Architecture, which included a plan for a star-shaped ideal city called Sforzinda in honour of Francesco Sforza and passionately argued for the centrally planned form.

Leonardo da Vinci, who was in Milan from around 1482 until the fall of the city to the French in 1499, was commissioned in 1487 to design a tiburio, or crossing tower for the cathedral, although he was not chosen to build it. However the enthusiasm he shared with Filarete for the centrally planned building gave rise in this period to numerous architectural drawings [pictured] which were influential in the work of Donato Bramante and others. Bramante's work in the city, which included Santa Maria presso San Satiro (a reconstruction of a small ninth-century church), the beautiful luminous tribune of Santa Maria delle Grazie and three cloisters for Sant'Ambrogio, drew also on his studies of the Early Christian architecture of Milan such as the Basilica of San Lorenzo.

The Counter-Reformation was also the period of Spanish domination and was marked by two powerful figures: Saint Charles Borromeo and his cousin, Cardinal Federico Borromeo. Not only did they impose themselves as moral guides to the people of Milan, but they also gave a great impulse to culture, with the creation of the Biblioteca Ambrosiana, in a building designed by Francesco Maria Ricchino, and the nearby Pinacoteca Ambrosiana. Many beautiful churches and Baroque mansions were built in the city during this period by the architects, Pellegrino Tibaldi, Galeazzo Alessi and Ricchino himself.

Empress Maria Theresa of Austria was responsible for the significant renovations carried out in Milan during the 18th century. She instigated profound social and civil reforms, as well as the construction of many of the buildings that still today constitute the pride of the city, like the Teatro alla Scala, inaugurated on 3 August 1778 and today one of the world's most famous opera houses. The annexed Museo Teatrale alla Scala contains a collection of paintings, drafts, statues, costumes, and other documents regarding opera and La Scala's history. La Scala also hosts the Ballet School of the Teatro alla Scala. The Austrian sovereign also promoted culture in Milan through projects such as converting the ancient Jesuit College, in the district of Brera, into a scientific and cultural centre with a Library, an astronomic observatory and the botanical gardens, in which the Art Gallery and the Academy of Fine Arts are today placed side by side. Milan was also widely affected by the Neoclassical movement in the late-18th and early-19th centuries, transforming its architectural style.

Napoleon Bonaparte's rule of the city in the early 19th century produced several fine Neoclassical edifices and palaces, including the Villa Reale, or often called the Villa del Belgiojoso (not related to the Palazzo Begiojoso). It is situated on Via Palestro and near to the Giardini Pubblici and it was constructed by Leopoldo Pollak in 1790. It housed the Bonaparte family, mainly Josephine Bonaparte, but also several others, such as Count Joseph Radetzky von Radetz and Eugène de Beauharnais. It is often regarded as one of the best types of Neoclassical architecture in Milan and Lombardy and is surrounded by an English landscape garden. Today, it hosts the Galleria d'Arte Contemporanea (English: Gallery of Contemporary Art) and it is lavishly decorated inside with ornate classical columns, vast halls, marble statues and crystal chandeliers. The Palazzo Belgiojoso was also a grand Napoleonic residence and one of the finest examples of Milanese Neoclassical architecture. There are also several other important Neoclassical monuments in the city include the Arco della Pace or the Arch of Peace, sometimes called the Arco Sempione (Sempione Arch) and is situated in Piazza Sempione right at the end of the Parco Sempione. It is often compared to a miniature version of the Arc de Triomphe in Paris. The work on the arch began in 1806 under Napoleon I and it was designed by Luigi Cagnola. Just like with the Arc de Triomphe, Napoleon's 1826 defeat at the Battle of Waterloo, halted the construction of the monumental arch, but Emperor Franz Josef (Francis Joseph) I of Austria ordered it to be completed, also as an honour to the Vienna Congress and peace treaty of 1815. It was completed by Francesco Peverelli on 10 September 1838. Another noted Neoclassic building in the city is the Palazzo del Governo, constructed in 1817 by Piero Gilardoni.

In the second half of the 19th century, Milan assumed the status of main industrial city of the peninsula and drew inspiration to the urbanization from other European capitals, center of those technological innovations that constituted the symbol of the second industrial revolution and, consequently, of the great social change that had been put in motion. The great Galleria Vittorio Emanuele II, a covered passage that connects Piazza del Duomo, Milan to the square opposite of La Scala, was built by Giuseppe Mengoni between 1865 and 1877 to celebrate Vittorio Emanuele II, the first king of united Italy. The passage is covered over by an arching glass and cast iron roof, a popular design for 19th-century arcades, such as the Burlington Arcade, London, which was the prototype for larger glazed shopping arcades, beginning with the Saint-Hubert Gallery in Brussels and the Passazh in St Petersburg. Another late-19th century eclectic monument in the city is the Cimitero Monumentale (literally, "Monumental Cemetery or graveyard"), which is found in the Stazione district of the city and was built in a Neo-Romanesque style by several architects from 1863 to 1866.

The tumultuous period of the 20th century also brought several innovations in architecture. A form of Art Nouveau, Art Deco and Fascist style is seen for the monumental city's Central Station (Stazione Centrale). The post-World War II period of reconstruction saw rapid economic growth that was accompanied by an increase in the population and the founding of new districts, but also for the strong drive for architectural renewal, has produced some of the milestones in the city's architectural history including Gio Ponti's Pirelli Tower (1956-60), the Velasca Tower (1956-58), the creation of new residential districts and, in recent years, the construction of the new exhibition centre in Rho and the urban renewal of once industrial areas, that have been transformed into modern residential districts and services, like the City Life business and residential center.