Cape Girardeau Commercial Historic District is a national historic district located in Cape Girardeau, Missouri. In 2000, the area listed was and included 17 contributing buildings. In a first increase, an 1891 contributing building at 101 North Main Street was added. The building was designed by Jerome B. Legg and Henry Ossenkop in the Romanesque style. In a second increase, three contributing buildings dating from 1870 were added. The two increases added 0 each to the original listed area.
It was listed on the National Register of Historic Places in 2000 with boundary increases in 2007 and 2008.