Ashtabula Regional Medical Center's history began because the community saw a lack of medical care when it was needed most. Its story began with a tragedy known as the Ashtabula Train Disaster of 1876. Community members recognized that a calamity of that magnitude could happen again and the community needed to respond. They combined resources, manpower, and expertise to start the first hospital in Ashtabula.

In 1882, a small emergency hospital opened to care for injured railroad workers. Work immediately began to raise funds for a permanent facility. On June 30, 1904, Ashtabula General Hospital opened its doors, at a cost to build of $14,500. Those early hospital founders rallied the community to furnish equipment and amenities for four wards, six private rooms, two operating rooms, administrative offices, a kitchen, a boiler room, a laundry room, and more.

The ghost of an old woman has been seen roaming the hallways in the early morning hours, usually between 1:00 AM and 4:00 AM. When she is seen by a witness, the security tapes do not show anything unusual. Slow moving footsteps have also been reported.