This house-museum contains 18th-century objects of fine porcelain in the Rococo-style Stucco Room, while the Flemish polyptych (panel painting divided into sections) is a major feature of the Black Room, a recreation of a 16th-century Northern-European environment. The museum’s collection of Gothic golden jewels is placed in the medieval Dante Study, while Baroque statues are found beside the antique staircase. Since the museum’s opening in 1881 for the Milan National Exhibition, the site has set a trend for other house-museums, including the U.S. Isabella Stewart Gardner, the Italian Antonio Borgogna and the French Jacquemart-Andrè.

In 1819, Giuseppe Poldi Pezzoli married Rosina Trivulzio, thus taking hold of splendid art collections. Gian Giacomo Poldi Pezzoli, his son, was born in Milan in 1822 and inherited one of the most beautiful palaces in the centre of Milan, with a vast garden decorated with statues and fountains. Giacomo, a Dante scholar and member of the Crusca Academy, was friends with many cultured men of his epoque, including poets Vincenzo Monti and Giuseppe Parini. In 1840, Giacomo spent some months in Paris, which deeply influenced his artistic taste, and after 1846 he began to collect art works. Later, during his travels across Europe, Giacomo visited the museums in London and Paris, which represented a combination of Fine and Decorative Arts, which inspired him to incorporate a vast selection of precious objects into his ensembles of paintings and sculptures. The works he gathered mainly came from the Renaissance and the Venetian 18th Century, including Medieval enamels and jewelry, carpets, tapestries, jewels, glassware and porcelains.

Giacomo’s collections were assisted by a handful of renowned connoisseurs, counsellors and antiquaries, including the famous art historian Giovanni Morelli, the painter and professor of the Brera Academy Giuseppe Bertini. It was Bertini who, following Giacomo’s death, became the first director of the museum and substantially augmented its painting and textile funds.

The museum’s collection is continuously being enlarged, mostly due to private collectors's donations, and has recently added a series of artworks, mechanical clocks and sundials, as well as laces and embroideries. During World War II, a bombing raid destroyed all main museums in Milan. The Poldi Pezzoli palace suffered severe damage, and although its works of art were previously transported to a safer place, damage to the palace and its decorations were beyond repair. The ceilings and windows collapsed, along with the stuccowork, the frescoed decorations and wooden engravings. Towards the end of the war, as reconstruction commenced, efforts were made to recreate the less heavily damaged parts of the museum, including the antique staircase and the Dante Study, and the site reopened in 1951.