Ulysses S. Grant, Jr. (1852-1929), son of the eighteenth President of the United States, arrived with his family in San Diego in 1893. He soon became interested in real estate and decided to build a hotel in San Diego in honor of his father. His wife, Fannie Chaffee Grant, purchased the Horton House, an existing hotel, in 1893. They planned to raze it and use the site for a new hotel. The Horton House remained in operation until it was torn down in 1905. Architect Harrison Albright (1866-1933) designed the new hotel, but because of lumber shortages resulting from the 1906 San Francisco earthquake and Grant's personal financial setbacks, construction was delayed. Mrs. Grant died in 1909, before the hotel was completed.

The U.S. Grant Hotel officially opened October 15, 1910. It had 437 rooms, 350 of which offered private baths, a roof garden and palm court, bivouac grill, dining room, and Grand Ballroom. It also included two large salt-water swimming pools fed by water piped up Broadway from the bay. Mr. Grant remarried in 1913, and he and his new wife became permanent residents of the hotel in 1919. Though Mr. Grant died in 1929, the second Mrs. Grant remained a resident until her death in 1942.

Throughout its history many celebrities have stayed at the U.S. Grant Hotel, including several dignitaries visiting San Diego for the Panama-California Exposition in 1915, and Charlie Chaplin in April 1917. Baron Long, an entrepreneur who held interests in Agua-Caliente Hotel and Spa in Tijuana and the Biltmore in Los Angeles acquired partial ownership in 1919. He touted the Biltmore and Grant as ideal places to stay while visiting across the border where gambling and alcohol were still legal. Long elaborately redesigned much of the Grant Hotel's lower level in the late 1920s. In 1926, radio towers were erected on the roof and much of the eleventh floor was converted to a radio station from which KFVW broadcasted.

Though the hotel did not prosper during the Great Depression, it still attracted guests. The 1935 California-Pacific International Exposition in Balboa Park brought many visitors, including President Franklin D. Roosevelt. During WWII, some of the Grant's guest accommodations became quarters for servicemen and their families, and the hotel became a popular meeting place for sailors. Because of constant overcrowding, the Grant even sold blankets to those willing to sleep in the hallways. In 1944, Joseph W. Drown bought the hotel for $3 million. Since then it has had many owners, including Loyola University (1945), Pacific Mutual Life Insurance Company (1950), M. Bert Fisher (1958), Harry Woolf and Daniel Bernstein (1963), Vernon E. Shipp (1964), and Roy Lake (1971).

In the mid-1950s, during a tourism boom, the Grant again underwent a major renovation. The Palm Court and roof garden were enclosed and became the spacious and modern Palm Ballroom. The fountain from the Palm Court was removed to the Agua-Caliente Racetrack. The goal of renovation had been to make the hotel more accommodating to automotive travelers and family vacationers, but these years also saw the growth of Mission Valley's hotel industry, just a few miles northwest of downtown San Diego, which lured many guests away from the Grant's downtown location.

In 1969, six women held a sit-in at the Grant's restaurant, the Grill, in order to protest its practice of not allowing women patrons to dine at the restaurant before 3:00 p.m. This led to a discrimination lawsuit in 1972 and '73.

The hotel was scheduled for demolition in 1979, but Christopher Sickels of the CDS Grant Corporation purchased it, and made plans to once again make major renovations. In July of that year the U.S. Grant Hotel was added to the National Register of Historic Sites. The hotel closed from August 1982 through December 1985 until renovations were completed.

While these renovations brought back much of the hotel’s original elegance, financial difficulties still plagued it. In December 1993, Grand Heritage Hotels International acquired ownership. That company also renovated the hotel, and in 1994 the Grant Hotel became the 104^th member of the elite Historic Hotels of America Program under the auspices of the congressionally charted National Trust for Historic Preservation. In June of 2001, Wyndham International purchased the hotel and additional renovations were completed. Finally, in December 2003, the Sycuan Band of Kumeyaay Indians purchased the hotel for $45 million, returning this parcel of land to its original inhabitants' ancestors. It is still in operation.