Domenico Ghirardelli, born in 1817 in Rapallo, Italy, was apprenticed to a candy maker at an early age. At the age of twenty, he sailed to Uruguay with his bride to establish himself in the South American chocolate trade. A year later, he sailed around Cape Horn to Lima where he opened a confectionery store next to a cabinet shop owned by James Lick.

In 1847, Lick left Lima to seek his fortune in San Francisco. He carried with him six hundred pounds of Ghirardelli's chocolate. Two years later, enticed by gold at Sutter's Mill, Ghirardelli sailed for California, leaving his second wife behind. He became a merchant in the Mother Lode foothills of the Sierra Nevada selling supplies and confections to miners. Soon he opened his first store in San Francisco at Broadway and Battery.

Ghirardelli's San Francisco store was burned by the 1851 fire which destroyed some fifteen hundred buildings. In 1852 he opened Ghirardelli & Girard on the corner of Kearny and Washington. A year later, he moved his successful operation to 415 Jackson Street (San Francisco Landmark 15).

The company purchased the Pioneer Woolen Mill in 1893 and moved operations to the current site of Ghirardelli Square. A year later, Domenico died in Italy while visitng Rapallo.

In 1900, the company built the Cocoa Building and sold its coffee and spice business to concentrate on chocolate and mustard. All buildings survived the 1906 Earthquake and Fire undamaged and with only a few days business interruption. A decade later, three new buildings were added to the complex: the Power House, the Apartment Building, and the Clock Tower, the latter inspired by Chateau de Blois in France. In 1923, the Cocoa Building acquired two more floors and the fifteen-foot Ghirardelli sign familiar to all who sail the San Francisco Bay.

In the 1960's, the buildings were converted for use as retail stores, restaurants and offices. Manufacturing operations moved to to San Leandro, California. (At that time, the Ghirardelli brand was owned by Golden Grain Macaroni Company. It has since been owned, in turn, by Quaker Oats Company, then a private investment group, then Lindt and Sprungli Chocolate of Switzerland.)