The Marietta & Cincinnati Railroad was originally established in 1845 as the Belpre & Cincinnati Railroad. It was to connect Belpre, Ohio with Cincinnati, Ohio. The company overseeing construction of the line chose to send the railroad line from Wheeling, Virginia (modern-day West Virginia) to Marietta, Ohio, rather than through Belpre. The Marietta & Cincinnati Railroad went bankrupt in 1857 after completing only 157 miles of track.
Although the original company collapsed, during the 1860s construction began again on the Marietta & Cincinnati Railroad. By 1866, the line had reached Cincinnati, crossing Ohio through the south-central part of the state. The line prospered during the late 1860s and the early 1870s, as the iron producing regions of Ohio in Jackson and Hocking Counties now had an easier means of shipping the iron ore to Cincinnati. Before the Marietta & Ohio's completion, most iron ore produced in Ohio came from the southern part of the state near the Ohio River. The line also provided southern Ohio residents a quicker means of traveling to Cincinnati. Numerous suburbs were established on Cincinnati's outskirts, and residents rode trains to work in the downtown portion of the city. In 1880, the Baltimore & Ohio Railroad purchased the Marietta & Cincinnati line. The Marietta & Cincinnati became known as the Cincinnati, Washington & Baltimore Railroad at this point. This line remained in operation until the early 1900s, when the Baltimore & Ohio shifted its operations to a track along the Ohio River.