Cass Gilbert was born on November 24, 1859 in Zanesville, Ohio to Samuel Augustus Gilbert and Elizabeth Fulton Wheeler Gilbert. The family moved to St. Paul Minnesota in 1868, and in 1878 Gilbert went to study architecture at Massachusetts Institute of Technology. After traveling and studying in Europe, he joined the New York office of McKim, Mead & White in 1880. In 1882, he was sent to St. Paul to open a branch office for McKim, Mead & White and to oversee the building of depots, terminals, and hotels for the Northern Pacific Railroad. Within two years, the office collapsed and Gilbert formed a partnership with James Knox Taylor in St. Paul that lasted until 1892. Gilbert produced churches and houses in Minnesota and was a recognized architect when he won a competition to design the Minnesota State Capitol in 1895.

In 1899, Gilbert returned to New York City and received a number of significant commissions. He won a competition to design the United States Custom House (1901-1907) and designed the 24 storied building at 90 West Street (1905-1907) in Manhattan. From 1911-1913, Gilbert worked on the Woolworth Building. At 55 stories tall, it was the tallest building in the world from 1913 to 1930 and became one of Gilbert's most famous designs. Other buildings in New York designed by Gilbert include the New York Life Insurance Company Building (1925-1928) and the US Courthouse (1936), which was completed after his death. Gilbert also completed designs for the George Washington Memorial Bridge (1927-1931) that proved to be too expensive and were never used.

Gilbert also became known for his work on the Art Building in the Louisiana Purchase Exposition in 1904 which eventually became the St. Louis Art Museum. He also designed the St. Louis Public Library (1907-1912) and the Detroit Public Library (1913-1921). His work in Washington D.C. included the US Treasury Annex (1918-1919), the US Chamber of Commerce (1924-1925), and the US Supreme Court Building (1933-1935).

Gilbert was active in art and architectural organizations. He was appointed by President Theodore Roosevelt as chairman of the Council of Fine Arts. He was made a member of the Commission of Fine Arts by President Taft and reappointed to the post by President Woodrow Wilson. He was a long time member of the American Institute of Architects and served as its president from 1908-1909. In 1919 he resigned his membership from the AIA after disputes with the leadership of the organization. He was also a long time member of the National Academy of Design and served as its president from 1926-1932. He also served as a member of the National Institute of Arts and Letters.

Gilbert was recognized in America and abroad for his architectural work. He received honorary degrees from the University of Michigan, Oberlin College, and Middlebury College and was awarded the Society of Art and Sciences Gold Medal Award in 1930. In Europe, he was made an honorary member of the Agricultural Society of the University of Liverpool and an honorary foreign member of the Royal Academy of Arts. He was also decorated with the French Legion of Honor.

In 1887, Gilbert married Julia Tappan Finch, the daughter of a wealthy attorney from Milwaukee. Together they had three children: Cass Gilbert Jr., Emily Finch, and Julia Swift who became the wife of Charles Morgan Post. The family owned many properties including places in Manhattan and Connecticut. Gilbert was active in various social clubs including the Century Club and the Union Club. Gilbert died on vacation in Brockenhurst, England in 1934 at the age of 75. Cass Gilbert Jr. worked as an architect in his father's office and finished many of the office's projects after his death.