Smyrna was originally called Duck Creek Cross Roads and received its current name in 1806 after the Ancient Greek seaport of Smyrna in present-day Turkey. The town was located along the north-south King's Highway. Smyrna was originally a shipping center along the Duck Creek and was the most important port between Wilmington and Lewes, shipping grain, lumber, tanbark, and produce to points north. After the shipping industry collapsed in the 1850s, the town would continue to be an agricultural center.
Another account of Smyrna's name goes back to the Second Great Awakening of 1806 to 1807 when Methodist preacher Frances Asbury preached a sermon on the Church at Smyrna from Revelation 2 to the local Methodist society. The sermon was so well received that the residents changed the name of the town to Smyrna in honor of the sermon.