Began his career at the age of 20 as a post-war civil engineer, working on rebuilding the railroad in the war-ravaged area of his youth. This work eventually brought him to Chicago, where he built miles of line as well as a number of shop terminals. Eventually, he became Chief Engineer of the Chicago and Western Indiana Railway.

After long consideration, he founded his own engineering/consulting practice, and was eventually elected Chief Engineer of the Chicago Sanitation and Ship Canal . He oversaw the entirety of the fourteen year project, which cost over 60 million dollars and was, at the time, the largest artificial water channel ever built. As a result, he was awarded a gold medal at the Paris Expo of 1900.

In 1908, Isham was invited by President Roosevelt to be one of six engineers to examine and advise concerning design plans for the Panama Canal.

In 1910, in recognition of his professional attainments, the University of Illinois awarded him the degree of "Doctor of Engineering," while Washington and Lee University conferred upon him the degree "Doctor of Commercial Science." Later, the Franklin Institute in Philadelphia awarded him the Elliott Cresson Medal, their highest honor, in recognition of his "Distinguished Achievement in the Field of Civil Engineering."

At the onset of World War I, Mr. Randolph was appointed to the office of President of the Citizens Unit of the 108th Engineers, and was instrumental in organizing that regiment.

In his personal life, Mr. Randolph married Mary Henry Taylor in 1882, and theirs was reputed to be a happy and inspiring union which produced three successful and admirable sons: Robert Isham, a consulting engineer who served as a Major in France, commanding the 535th Engineers; Oscar DeWolf, who served as Rector of St. Mary's on the Highlands in Birmingham, Alabama and also served in the Machine Gun Corps, 10th Division, during World War I; and Spottiswoode Wellford, engineer and manufacturer.