At the age of fourteen, Van Horne began working on railroads, serving in various capacities on the Illinois Central Railroad until 1864. He went on to work for the Chicago and Alton Railway, serving as general superintendent 1878–1879. In 1882, he was appointed general manager of the Canadian Pacific Railway, becoming its vice-president in 1884 and president in 1888, finally becoming chairman of the board in 1899. He is most famous for overseeing the major construction of the first Canadian transcontinental railway, a project that, under his leadership, was completed in under half the projected time.