First settled by the Dutch in the 17th century, present day Odessa was originally called Appoquinimink, after the creek on which it lies. British settlers gradually replaced the Dutch, and in 1664 the Appoquinimink area was confiscated and deeded to a Captain Edmund Cantwell. In 1731, his enterprising son, Richard Cantwell, built a toll bridge over the creek. The adjoining village gradually became known as Cantwell's Bridge.

The first industry in the town was a tannery built in 1767 by William Corbit. A blacksmith shop was opened in 1817 to serve the approximately 30 houses in the town, and various agricultural, manufacturing and cannery industries followed. By 1825, the town had grown into a major river port, shipping grain and farm produce from the surrounding area to ports along the Delaware River. From 1820 to 1840, over 400,000 bushels of grain were shipped from Cantwell's Bridge annually.

In 1855, with the completion of the railroad into nearby Middletown, the grain-shipping trade which supported Cantwell's Bridge collapsed, and the bustling community began to decline. The citizens voted to change the town's name to Odessa, after the great Russian grain port, in a vain attempt to revive their river shipping trade. But Odessa slipped slowly into disrepair and decay.

In 1938, H. Rodney Sharp purchased and restored the Corbit-Sharp House, now owned and maintained by the Historic Odessa Foundation. His efforts sparked an interest in the architectural treasures of Odessa, and marked the beginning of its rebirth as a piece of Delaware history.

Today, tiny Odessa's tree-shaded streets are lined with lovingly restored 18th and 19th century homes.