The area of Meldola has been inhabited since very ancient times. The Romans built here a large aqueduct (still existing under the ground) which served the military port of Classis. To the 5th-6th century belongs a large patrician villa which is now under the historical centre.
In the late 19th century and in the first years of 20th century, Meldola was well known for its production of silk. The main activities include agriculture and the manufacture of furniture. A recently built oncology hospital provides research into cancer and care for cancer patients.