The original CH&D was founded by John Alexander Collins, who was born on June 8, 1815, in Staffordshire, England.

The railway received a charter from the State of Ohio on March 2, 1846, as the "Cincinnati and Hamilton Railroad".

In 1886 the CH&D was among the railroads controlled by the financial speculator Henry S. Ives before his spectacular collapse the following year.

Successor CH&D built a larger structure on the site, which continued to be used by the Baltimore and Ohio at least into the 1950s.

The passenger depot followed a similar pattern, but was located farther north, between East Wayne Street and the Pennsylvania Railroad tracks.