The Chicago and Eastern Illinois Railroad was organized in 1877 as a consolidation of three others -- the Chicago, Danville and Vincennes Railroad (Chicago to Danville, November 1871), the Evansville, Terre Haute and Chicago Railroad (Danville to Terre Haute, October 1871) and the Evansville and Terre Haute (Terre Haute to Evansville, November 1854). Intended to merge or purchase railroads that had built lines between the southern suburbs of Chicago and Terre Haute, Indiana through Danville, Illinois, the C&EI constructed a new line from Chicago to a Mississippi River connection in extreme southern Illinois at Thebes.

The management of the Chicago and Eastern Illinois and the Chicago and Indiana Coal Railway ("the Coal Road" or C&IC) became intertwined and eventually a connection was built between the two railroads between Goodland, Indiana (on the C&IC) and Momence (on the C&EI). By 1894 the Eastern had merged the C&IC. The C&EI continued this vigorous growth into the next decade.

In 1902, the Frisco purchased a controlling interest in the Chicago and Eastern Illinois and continued building; first a connection between the two railroads at Pana, Illinois, next extending the line in Indiana to Evansville and a connection with the Ohio River.

However, in 1913 financial problems led to the collapse of the Frisco, and the Eastern was once again on its own by 1920. The C&EI spun off a variety of their lines, including the "Coal Road" (which became the Chicago, Attica and Southern Railroad). The C&EI did not survive the Great Depression intact, entering bankruptcy in 1933, re-emerging just before World War II in 1940. The railroad continued its brisk growth once again, gaining access to St. Louis, Missouri in 1954.

The Missouri Pacific and the Louisville and Nashville began carving up the Chicago and Eastern Illinois between them starting in 1961.

The line directly south of Chicago to near Danville was actually purchased by both railroads (and to this day continues to be owned and operated jointly by MoPac and L&N's successors, Union Pacific Railway and CSX Transportation respectively), but Missouri Pacific eventually merged the Eastern in 1976.