Renwick was not formally trained as an architect. His ability and interest in building design were nurtured through his cultivated background, which granted him early exposure to travel, and through a broad cultural education that included architectural history. He learned the skills from his father. He studied engineering at Columbia, entering at age twelve and graduating in 1836. He received an M.A. three years later. On graduating, he took a position as structural engineer with the Erie Railroad and subsequently served as supervisor on the Croton Reservoir, acting as an assistant engineer on the Croton Aqueduct in New York City.
Renwick received his first major commission, at the age of twenty-five, in 1843 when he won the competition to design Grace Church, an Episcopal church in New York City, which was executed in the English Gothic style. In 1846 Renwick won the competition for the design of the Smithsonian Institution Building in Washington, DC. Built between 1847 and 1855, the many-turreted building, generally referred to as ‘the Castle’, was designed in the Romanesque style, as requested by the Board of Regents of the Smithsonian, and was built of red sandstone quarried in Seneca, Maryland. It was a major influence in the Gothic revival in the United States.
In 1849, Renwick designed the Free Academy Building (City College of New York), New York City, at Lexington Avenue and 23rd Street. It was one of the first Gothic Revival college buildings on the East Coast.
Renwick went on to design what is considered his finest achievement, and his best-known building, St. Patrick's Cathedral, New York, on the corner of Fifth Avenue and 51st Street. He was chosen as architect for the cathedral in 1853, construction began in 1858, and the cathedral opened in May 1879. The cathedral is the most ambitious essay in Gothic that the revival of the style produced and is a mixture of German, French, and English Gothic influences.
During the same period of his triumph of St. Patrick's Cathedral, he designed the first chapter house of St. Anthony Hall/Delta Psi, the secret fraternal college society which had founded at Columbia University in 1847. Though the 1879 structure is marred now by a storefront at the street level, floors two through four still rise up at 29 E. 28th Street, New York. Christopher Gray in the New York Times in 1990 wrote that "Old photographs show a high stoop arrangement with the figure of an owl on the peeked roof and a plaque with the Greek letters Delta Psi over the windowless chapter room. In 1879, The New York Tribune called it French Renaissance, but the stumpy pilasters and blocky detailing suggest the Neo-Grec style then near the end of its popularity." In 1899 the fraternity occupied a new chapter house at 434 Riverside Drive that echoed many of the motifs of Renwick's structure, and Renwick's 28th Street building was for a few years kept as a clubhouse for graduate members. At that time a newspaper account described it as a "perfect Bijou of tasteful decoration".
Among other buildings that Renwick designed was the Corcoran Gallery of Art (now home to the Smithsonian's Renwick Gallery), in the Second Empire style, in Washington D.C. (1859-1871). Other commissions included the first major buildings on the campus of Vassar College in Poughkeepsie, New York (1861-1865), including the Main Hall (1860); Saint Bartholomew's Church (1871-1872) in New York City; All Saints' Roman Catholic Church (1882-1893) in Harlem in the Victorian Gothic style; many mansions for the wealthy of New York; banks; the Charity and Smallpox Hospitals on Roosevelt Island; the main building of the Children's Hospital on Randall's Island; the Inebriate and Lunatic Asylums on Ward's Island; and the former facade of the New York Stock Exchange. Renwick was also supervising architect for the Commission of Charities and Correction. A small group of Renwick's architectural drawings and papers are held by the Avery Architectural and Fine Arts Library at Columbia University.
Renwick also designed the bell tower of the Cathedral of St. Augustine, Florida. The work was commissioned by Standard Oil partner Henry M. Flagler who was building luxury hotels in the historic city at the time. Renwick and his wife Anna Aspinwall lived and owned property in the lighthouse area of St. Augustine on Anastasia Island.