Established with nine beds in 1885, Good Samaritan moved in 1911 to what was then a residential district located on Orange Street. Next door at 1213 Orange Street stood the Victorian-style home of Clara Shatto, who donated the land a mile west that became Lafayette Park.

After Orange Street was expanded and renamed Wilshire Boulevard, Good Samaritan grew with the city, adding major new buildings in 1927 and 1953 in various styles.

Senator Robert F. Kennedy of New York died at the hospital in June 1968 after being shot down the street at the Ambassador Hotel, moments after winning the California Democratic presidential primary.

In 2011, an $80 million expansion project was proposed, due to be completed in 2015.