The Nickerson Mansion was given the nickname “Marble Palace” due to the 17 different types of identified marble used in construction. In addition to onyx and alabaster, marbles from France, Italy, Belgian and the United States can be found throughout the museum.

The Driehaus Collection of Fine and Decorative Arts is a diverse collection of European and American artifacts created predominantly between 1880 and 1920. The Driehaus Collection supplements the works of the mansion's original architects and interior designers.

Samuel Mayo Nickerson came to Chicago in the late 1850s with his bride Mathilda. After earning his first fortune in the liquor industry, Nickerson moved into banking and became president of the First National Bank in 1867. He commissioned the architectural firm of Burling & Whitehouse to build this mansion in 1879, replacing the original home destroyed by the Great Chicago Fire.

There are a number of original furnishings still on display in the museum, including seat furniture in the drawing room; the settee, rocking chair, and three side chairs in the front parlor; the chandelier and chairs in the library; plus Samuel M. Nickerson’s original dining room table.

W. A. Fiedler was responsible for the interior designs of the Nickerson Mansion's carved woodwork, cabinets, and marble. Fiedler also contributed to the decoration of the Germania Club, the Hegeler-Carus Mansion, and other notable Chicagoland buildings.

Structurally, the Nickerson Mansion features brick-bearing wall and masonry arches supported by cast iron beams. Upon its completion, the building was described as "one of the few fire-proof houses in the city."

Originally the home was lit by a mixture of gas and electric lighting. An 1888 Chicago Tribune article about a Nickerson Christmas party describes the use of electricity in the house. The home's second owner, Lucius Fisher, installed Edison bulbs in the marble cornices of the first two floors.

As president of First National Bank, Samuel Mayo Nickerson appreciated the security provided by a safe. The marble-covered safe on the first floor blends into the surrounding walls, complementing the rich interiors and bewildering potential troublemakers. Visitors can ask to see this safe's interior.

The works of Louis Comfort Tiffany, the premier decorative artist of the Gilded Age, are prominently displayed throughout the Museum. Stunning examples include the urn-shaped turtleback glass chandelier in the sitting room and Lily table lamp in the drawing room. The house also contains custom stained-glass windows and fireplaces, designed by other prominent artists of the day.