Little is known about the history of the city in ancient times. In the first quarter of the 1st century AD, the geographer Strabo mentions Xantheia, to the east of Lake Vistonis, along with Maroneia and Ismaros as one of the cities of the local Thracian tribe of the Cicones. Various views have been put forward on the identification of the ancient city, but the lack of archaeological data does not answer the question of whether ancient Xantheia stood on the site of the Byzantine castle-city.

The earliest reliable reference to Byzantine Xantheia is found in the minutes of the Council of Constantinople in 867, attended by George, the bishop of the city. As an episcopal see subject to the metropolitan see of Trajanopolis, it also appears in later written sources of the first half of the 10th century, indicating the city’s importance to the region of Thrace.

In the following centuries, from the end of the 12th century onwards, the city is very frequently mentioned by contemporary historians, as it played a leading role in the turbulent political developments in Thrace, a region of vital importance to the Byzantine Empire. In August 1185, the city was sacked, probably by the Normans, who occupied and pillaged the area from Philippi and Christopolis (present-day Kavala) to Mosynopolis. In 1198, the sources mention a raid against Xantheia by the Bulgarian boyar Ivanko (Ivangos), who had established his own hegemony in Rhodope and Central Thrace.

In the summer of 1204, shortly after the Sack of Constantinople by the forces of the Fourth Crusade, Count Baldwin I of Flanders launched a campaign against Thrace. Xantheia, led by a certain Senacherim, attempted to resist Baldwin’s expansionist ambitions, but without success. Xantheia was then ceded, along with Thessaloniki, to the Frankish knight Geoffrey I of Villehardouin. In 1205/6, whereas the important castle-cities of Thrace, such as Mosynopolis and Peritheorio, were destroyed by the Bulgarian ruler Kalojan (Ioannitza or “Skyloioannes”), Xantheia was spared, probably because the Via Egnatia, which the Bulgarian ruler followed on his way to Thessaloniki, did not pass through the city. Shortly after 1224, the city was conquered by Theodore Komnenos Doukas, ruler of the Despotate of Epirus. He was defeated in a battle against the Bulgars in 1230 and thus Xantheia came under the rule of the Bulgarian Tsar John Asen II. In 1241 Xantheia was restored to the Byzantine sphere of influence. In the autumn of 1264, Emperor Michael VIII Palaiologos wintered with his army in Xantheia during his campaign against the Despot of Epirus Michael II. His decision to stay in the city is probably linked to the appearance of a comet; in Byzantine times, superstitions associated with natural phenomena were very powerful. At the end of 1327, during the Byzantine Civil War, the city was again a stopping-point for the army of Andronikos III Palaiologos. The fact that the imperial troops were stationed in Xantheia indicates that it had the necessary infrastructure to house and feed them.

In the 14th century, Xantheia is referred to in the sources both as a polichnion, a small town, and as a polis, a large urban centre. During this period, Xantheia was the seat of a domestikos, a senior Byzantine official. It seems, therefore, that it had become the seat of a large administrative district. In 1307, Ferdinand Ximenes d’Arenós, one of the leaders of the Catalan Grand Company, sought refuge in Xantheia after the deadly battle near Peritheorion between the two factions of the Catalan army hired by the Emperor Andronikos II Palaiologos to help him fight the Turkmens in Asia Minor and the Bulgars in Thrace. Before 1316, under Andronikos II Palaiologos, the episcopal see of Xantheia was elevated to an archiepiscopal see, and before the mid-14th century it became a metropolitan see. The church of the city seems to have been prosperous enough to make a financial contribution to the Patriarchate of Constantinople comparable to, or even greater than, that of other neighbouring cities.

Xantheia was at the forefront of the conflicts during the Byzantine Civil War of 1341-1347, between the Palaiologoi and John Kantakouzenos. In late 1347 or 1348, it was included in the region between Didymoteichon and Christopolis, which John Kantakouzenos ceded to his son Matthew. From 1369 to 1371, Xantheia passed into the hands of the Serbian rulersfor a brief period. In 1371, after the Serbs were defeated by the Ottomans in the Battle of Marica, or shortly afterwards (1373), Xantheia was conquered by the Ottomans.

During the Ottoman period, Xantheia survived under its Byzantine name, as it is referred to in the sources as Ksansi, Escise, İskeye and Eksya. During this time, the city retained its Christian character and became the only settlement centre between Adrianople and Thessaloniki where the Christian population outnumbered the Muslim population. It is telling that in the reign of Bayezid II (1481-1512), there were 483 Christian households in Xanthi, compared to 22 Muslim households, while in 1531 the Christian households had increased to 586, as opposed to the Muslim households, which had decreased to 19. The predominance of the Christian population of the city was largely due to the founding by the Ottomans of the city of Genisea, a short distance from Xanthi. The majority of the Muslims who had settled in the Xanthi plain lived there, and Genisea became the economic and administrative headquarters of the Ottomans in the region.

In the mid-16th century, the Zakynthian scholar Pachomios Roussanos mentions that Xanthi is still a Greek Christian centre. In the 17th century, it seems that the Muslim population of the city recovered demographically, based on the description of the Ottoman traveller Evliya Çelebi, who visited the city in the late 1670s, and reported that it had 500 houses, with half the population being Christian and the rest Muslim. He mentions Xanthi as being the seat of a number of officials of the Ottoman administration, such as the kadi, the Sheikh-ul-Islam (Turkish Şeyḫülislām, a high court official) and others.

The first attestation of the high quality of the region’s tobacco, which was considered among the best and most expensive in the Ottoman Empire, is dated to 1715. From the late 18th and early 19th century onwards, tobacco became the most important crop in the region, resulting in a great economic boom for Xanthi. The tobacco of Xanthi became highly sought after at the court of the Sultan and quickly crossed the borders of the Empire and, via the ports of Porto Lagos and Kavala, reached the markets of the Danubian Principalities, Russia, Austria and Egypt. The city’s numerous hans also attest to its importance as a commercial centre of the region.

In 1829, a series of strong earthquakes with their epicentre in Drama caused great destruction in Xanthi. There followed a long period of prosperity for the city between 1830 and 1845, when luxurious residences and large warehouses for the collection, storage and processing of tobacco were built. At the same time, on the initiative of the dynamic Metropolitan Bishop of Xanthi, Eugenios (1831-1848), magnificent new churches were rebuilt on the site of those destroyed by the earthquakes, around which the Christian quarters of the city were organised and rebuilt.

In 1872, after the destruction of Genisea in a great fire (1870), Xanthi became the seat of the kaza of the same name and shot to the peak of its prosperity. The Thessaloniki–Constantinople/Istanbul railway line, to which the city was connected in 1891, contributed to this development. After 1870, Xanthi experienced a second phase of construction, in which builders from Western Macedonia and Epirus played a leading part. During this period, beautiful, spacious houses, schools and new tobacco warehouses were built, the last employing large numbers of workers.

During the First Balkan War in 1912, Xanthi fell to the Bulgarians, and with the Treaty of Bucharest (17/28 July 1913) it was recognised as a Bulgarian possession. The Bulgarian occupation, which was particularly brutal for the inhabitants, ended on 4 October 1919, when the city was occupied by the Greek 9th Infantry Division. Under the Treaty of Sèvres (28 July/10 August 1920), the region of Xanthi was ceded to Greece. After the Asia Minor Catastrophe in 1922, the city’s population was boosted by refugees from Asia Minor, Eastern Thrace and Bulgaria. The city experienced a third harsh Bulgarian occupation during the Second World War (1941-1944).