In 1880, Gilbert went to Europe. He made drawings of buildings and their details in sketchbooks, a habit he kept his entire working life. When he didn't find work in London, he returned to New York and joined the firm of McKim, Mead & White. For them, he returned to St. Paul in 1882 as their representative in the West. His patron there was Henry Villard, owner of the Northern Pacific Railroad. (In 1882, McKim Mead & White had designed the Villard Houses in NYC.) Gilbert planned to oversee the building of depots, terminals and hotels for the railroad, but Villard's business fell apart.

Gilbert formed a partnership (1885) with his friend James Knox Taylor. Rather than be a mere builder, Gilbert oversaw the planning and development of a project. Gilbert recognized the importance of connections, and he developed them; he married the daughter of a wealthy attorney from Milwaukee. His architectural firm built close to 50 homes, commercial buildings and churches. Many survive including: the U.S. Supreme Court Building (with John R. Rockart) and the Essex County Courthouse in Newark, NJ. In New York, surviving buildings include: the U.S. Customs House; the U.S. Courthouse; the George Washington Bridge; the New York Life Insurance Building; the American Academy of Arts and Letters at Audubon Terrace and the Woolworth Building (when built, the tallest building in the world). He designed state capitols, including those of Minnesota, West Virginia, and Arkansas; and libraries in St. Louis, Detroit and New Haven, CT. In Minnesota, he caused a controversy when he insisted on the use of Georgian marble for the Minnesota State Capitol project, rather than locally quarried stone. The dispute ruined his business in Minnesota, although the building was built to his design and completed in 1905.

Gilbert was a founder of the Architectural League, a member of the National Academy and a president of the America Institute of Architects. He was a member of the Society of Cincinnati, the Pilgrims and Alpha Rho Chi. He received gold medals for the Academy of Arts and Sciences and the National Institute of Arts and Letters. He was a member of the Century, Union, University, Metropolitan and Washington clubs. Gilbert worked on many buildings with his son Cass Gilbert Jr. He supported the erection of pillars of the Parthenon in Athens, Greece, and raised money for that cause. He died from a heart attack just before he was to embark from England to the United States.