The line opened north to Columbus in August 1852, and on September 1, 1852, it began operating the Rushville and Shelbyville Railroad under lease.

Although it was successful for more than a decade, it went into decline, was sold at foreclosure on March 27, 1862, and renamed the Indianapolis and Madison Railroad (I&M).

The successor company abandoned the M&I's 10.09 miles (16.24 km) of trackage between Columbus and Edinburgh in 1864 and began running over the Jeffersonville Railroad's nearby tracks.

[2] Organized on April 30, 1866, for the purpose of uniting the two lines, the Jeffersonville, Madison and Indianapolis Railroad Company (JM&I) absorbed the Indianapolis & Madison the next day, with the Jeffersonville Railroad being officially merged in on June 1 of that same year, upon the filing of the Articles of Consolidation.

[citation needed] On May 22, 1868, the Reno Gang held up the JM&I Railroad train at Marshfield, Scott County, Indiana, and escaped with $90,000 in cash described as being in "new notes."