At the age of eight, Columbus Delano's family moved to Mount Vernon in Knox County, Ohio, a place he would call home for the rest of his life. After completing his primary education, he studied law and was admitted to the bar in 1831. He then set up his practice in Mount Vernon, going on to act as the prosecuting attorney for Knox County.

A member of the Whig Party, Delano became active in politics and in 1844 was elected to the United States House of Representatives as a Whig. After serving his two year term he chose not to run again, instead focusing on Ohio politics, launching an unsuccessful bid for the governorship in 1847.

With the demise of the Whig party, Columbus Delano became an Ohio delegate to the Republican National Convention in 1860, supporting Abraham Lincoln's nomination as President. The following year he served as State commissary general and in 1862 ran for the United States Senate, losing by only two votes. The next year, he was successful in a bid to become a member of the State house of representatives. After completing his term, Delano remained active in party politics and was appointed Commissioner of Internal Revenue in March of 1869. He served in that position until November 1, 1870 when President Ulysses S. Grant appointed him Secretary of the Interior.

With the Interior department's varied and diverse responsibilities increasing at a rapid rate, it had become a place with numerous administrative problems. For the department head, controlling the bureaus and shaping policy was a daunting task and during Delano's time as Secretary, he faced many problems but managed to last longer in the job than any other 19th-century incumbent. However, the corruption that permeated much of President Grant's administration became especially rampant in the Bureau of Indian Affairs during Delano's tenure, and it ultimately led to Delano resigning his position on October 19, 1875. Delano resigned because of evidence that his son, John Delano, had been given partnerships in surveying contracts over which the Interior Department had control.

During his tenure as Secretary of the Interior, the town of Delano, California, founded on July 14, 1873, was named in his honor. On his resignation from Grant's cabinet, Delano returned to Mount Vernon where for the next twenty years he served as president of the First National Bank of Mount Vernon. A long time trustee of Kenyon College in Gambier, Ohio where an LL. D degree had been conferred on him, he endowed Delano hall. His Lakeholm mansion, built in 1871 at the outskirts of Mount Vernon, is now part of Mount Vernon Nazarene University.

Columbus Delano died in 1896 and was interred in Mound View Cemetery in Mount Vernon, Ohio.