Beginning in the Roman Republic, Ephesus was the capital of proconsular Asia, which covered the western part of Asia Minor.

The original city of Ephesus was located on low ground, and was completely flooded by the sea. The city was rebuilt by Lysimachus, who destroyed the cities of Lebedos and Colophon in 292 BC and relocated their inhabitants to the new city.

The city bore the title of "the first and greatest metropolis of Asia." It was distinguished for the Temple of Artemis (Diana), who had her chief shrine there, for its library, and for its theatre, which would have been capable of holding 25,000 spectators. It was, like all ancient theatres, open to the sky; it was used initially for drama, but during later Roman times gladiatorial combats were also held on its stage. The population of Ephesus has been estimated to be in the range of 400,000 to 500,000 inhabitants in the year 100 AD, making it the largest city in Roman Asia and one of the largest cities of the day. Ephesus also had several major bath complexes, built at various points while the city was under Roman rule. The city had one of the most advanced aqueduct systems in the ancient world, with multiple aqueducts of various sizes to supply different areas of the city, including 4 major aqueducts.

Although sacked by the Goths in 263 CE, Ephesus remained the most important city of the Byzantine Empire after Constantinople in the 5th and 6th centuries. However, sackings by the Arabs in the year 700 and 716 spurred a quick decline: the city was largely abandoned when the harbour completely filled in with silt from the Kaystros river (today, Kucuk Menderes), despite repeated dredges during the city's history. (Today, the harbour is 5 km inland.) The loss of its harbor caused Ephesus to lose its access to the Aegean Sea, which was important for trade. When the Seljuk Turks conquered it in 1090, it was a small village. The Byzantines resumed control in 1100 and kept control of the region until the end of the 13th century. After a short period of flourishing under the new rulers, it was definitively abandoned in the 15th century.

    Ephesus was an important center for early Christianity. Paul used it as a base. He became embroiled in a dispute with artisans, whose livelihood depended on the Temple of Artemis there (Acts 19:23–41), and wrote 1 Corinthians from Ephesus. Later Paul wrote to the Christian community at Ephesus.

The Catholic Encyclopedia notes, "the Apostle and Evangelist John lived in Asia Minor in the last decades of the first century and from Ephesus had guided the Churches of that province...After Domitian's death the Apostle returned to Ephesus during the reign of Trajan, and at Ephesus he died about 100 AD at a great age". Ephesus was one of the seven cities addressed in Revelation (2:1–7).

There is also a letter written by Ignatius of Antioch to the Ephesians in the early 2nd century AD, that begins with, "Ignatius, who is also called Theophorus, to the Church which is at Ephesus, in Asia, deservedly most happy, being blessed in the greatness and fulness of God the Father, and predestinated before the beginning of time, that it should be always for an enduring and unchangeable glory" (Letter to the Ephesians).

The house of the Virgin Mary (Turkish: Meryemana, meaning "Mother Mary"), about 7 km from Selçuk, is believed to have been the last home of Mary, mother of Jesus and is a popular place of pilgrimage. Also nearby is the town of Meryemana.

The Church of Mary close to the harbor of Ephesus was the setting for the Third Ecumenical Council in 431, which resulted in the condemnation of Nestorius

                    
                                                                    The Roman Civic Library
 

    A part of the site, St. John's Basilica, was built in the 6th century AD, under emperor Justinian I over the supposed site of the apostle's tomb. It is now surrounded by a Turkish town, Selçuk.

It is a vast site, not yet completely excavated but what is visible gives some idea of its original splendour and the names associated with it are evocative of its former life. The theatre is huge and in a very outstanding position which dominates the view down Harbour Street leading to the harbour, long since silted up.

The Library of Celsus, whose façade has been carefully reconstructed from all original pieces, was built ca. 125 BC. by Gaius Julius Aquila in memory of his father, and once held nearly 12,000 scrolls. Designed with an exaggerated entrance — so as to enhance its perceived size, speculate many historians — the building faces east so that the reading rooms could make best use of the morning light. An underground tunnel, marked by the simple figures of a woman, a heart, and a price, leads from the library to a nearby building believed to have been a drinking establishment or brothel.

The Temple of Artemis, one of the Seven Wonders of the World, is represented only by one inconspicuous column, revealed during an archaeological excavation by the British Museum in the 1870s. Some fragments of frieze (which are insufficient to suggest the form the original) and other small finds were removed – some to London and some to the Archaeological Museum, Istanbul. Other edifices excavated include:

• The Odeon

• The Temple of Hermes

• The Temple of Domitian (once attributed to Serapis)

• The Theater

Selçuk's annual camel wrestling championship occurs at near Ephesus in the winter.