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The Central Pacific Railroad mogul Leland Stanford, Sr., (1824-1893) and his wife, Jane (1828-1905), were married in 1850. Leland Stanford came to California in 1852, and Jane ventured out from New York in 1858; original owner Shelton C. Fogus sold the house in 1858 to the Stanfords for $8,000, less than its assessed valuation; it was originally a two-story house, but the new owners enlarged it multiple times. Jane Stanford gave the property to the Roman Catholic Diocese of Sacramento in 1900, along with a $75,000 fund for its maintenance; the diocese used it as an orphanage, 1900-1932; beginning in 1932, the house was transformed into a home for girls of high school age; in 08/1936, the upper floor of Stanford House continued to serve girls of high school age, while the bottom floor was taken over By Sisters of Social Service, who utilized it as a settlement house; the original furniture remained in the residence in 1940. Due to its association with the Stanfords, the house was placed on the National Register of Historic Places in 1971, and, on 05/28/1987, made a National Historic Landmark, a designation given to the most significant historic buildings, structures or sites.

At the time of Stanford's election as California Governor (in late 1861), a 116-foot liberty pole was erected in front of the house.

Due to serious flooding in Sacramento in 12/1861-01/1862, the Stanford House was heavily damaged (the entire first floor had been submerged) and was renovated at that time. (Stanford needed a rowboat to attend his gubernatorial inauguration ceremonies at the Capitol Building on 01/10/1862.) This catastrophic flooding triggered massive public work projects including the rechanneling of the American River and the raising of Sacramento's streets between 1862-1872. (Flooding continued to plague the city; another flood in 1878 caused the passage of a comprehensive flood control plan in 1880.) In 1872, Stanford raised the ground floor up a story, to make a three-floor dwelling. Like many houses in the Sacramento area, it had raised foundations to remain above periodic flooding of the Sacramento and American Rivers. This renovation cost in the neighborhood of $45,000, $1,000 alone was set aside for a library; Architects, Page and Turnbull, renovated the Stanford House c. 2000;