The town has been inhabited for thousands of years, as it is one of the few places in all the Lower Danube that can be easily forded and thus be an easy link between the Balkans and the steppes of Southern Ukraine and Russia, north of the Black Sea.

Another theory of the history the settlement is that a group of Russian refugees (see Lipovans) settled there and founded the monastery, but soon became outlaws who were eventually caught.

The name Saka could in turn be derived from Romanian sacă/seacă, meaning "barren", however both the identification of the city with Isaccea and the etymology are mere speculations.

The initial "i" in the name was added during the Ottoman domination, due to the same feature of the Turkish language that transformed "Stanbul" to "Istanbul".

[20] Further attacks continued in the 3rd century, this time by the combined forces of the Dacian tribe of the Carpi and of the Goths, the decisive battle being probably in 247.

The violent invasions of the Carpi, who plundered the cities and enslaved their inhabitants, left behind many archaeological traces, including buried coin hoards and signs of destruction.

[21] The fortress of Noviodunum was probably destroyed during the raids of the Goths and Heruli, during the rule of Gallienus (267), buried hoards being found near it, including a larger treasure containing 1071 Roman coins.

[13][16] The raids left Noviodunum, like other urban centres in the area, depopulated, only returning to its original state toward the end of the 3rd century.

[21] During the rule of Constantine I (306-337), the Noviodunum fortress was rebuilt as part of a bigger project of restoring the Empire's borders along the Lower Danube.

The tomb of four Roman Christian martyrs, discovered in September 1971 in nearby Niculiţel, bears the names Zotikos, Attalos, Kamasis and Philippos.

[27] The Slavs began to settle in early 6th century and possibly the earliest reference to their settlement in the town is Jordanes' book (written in 551) The Origin and Deeds of the Goths, which mentioned Noviodunum as an extremity of the region were the "Sclaveni" lived.

[29] Around 950, Constantine Porphyrogenitus talks of six desert cities in the area, one being named Saka-katai, which could be the earliest mentioning of the town after it was lost to the migrating people during the Dark Age.

In 1036, the Pechenegs being driven southward by the Cumans, settled in Scythia Minor, including in this city, fact backed by archeological evidence, such as leaf-shaped pendants, characteristic to them.

At the time, the city was a local Muslim centre and the residence of the famous Turkish dervish Sarı Saltuk, who has been associated with Nogai Khan's conversion to Islam.

[36] Arab geographer Abulfeda mentioned the town, placing it in the territory of the "Al-Ualak" (Wallachs), having a population mostly Turkic and being ruled by the Byzantines.

[37] A Byzantine despotate existed in Northern Dobruja with Isaccea as its centre, which sometimes between 1332 and 1337 became a vassal of the Golden Horde of Nogais under the name "Saqčï".

In 1417, the town was conquered, together with other fortresses on the Danube, by the Ottomans,[40] who built a fort defended by a garrison as part of the Danubian frontier established by Mehmed I.

We killed 23,884 Turks and Bulgars without counting those whom we burned in homes or whose heads were not cut by our soldiers....Thus your highness must know that I have broken the peace with him [the sultan].

[43]In 1484, it was taken again by the Ottomans under Mehmed II, being included in the Silistra (Özi) Province, which comprised Dobruja, much of present-day Bulgaria, and later also Budjak and Yedisan.

Țepeș's massacre and destruction completely changed the ethnic composition and the appearance of Isaccea, which remaining throughout the 16th century a small, largely Christian, village.

[47] Sultan Osman II began a series of campaigns against the Cossacks and, as part of his fortification of the border, in 1620, a new fort was built in Isaccea, but in a different place.

In December of that year, The Times of London noted that "Isaktchi" had a fortified castle and a garrison of 1500 men, but that it was simply a "port of observation" on the river.

At the beginning of the Russo-Turkish War, 1877–1878, the Russians were able to take advantage of Romania's railways and mass a great number of troops in Galați.

4000 Russian troops crossed the Danube 14 km south of Măcin and were victorious on June 22, 1877, against the Ottoman garrison.

The first Russian unit crossed the Danube at Isaccea on the day when war was declared (August 27, 1916) and began their deployment toward Bulgaria, an ally of the Central Powers.

[59] In February 2022, during the Russian invasion of Ukraine, thousands of Ukrainians crossed by ferry into Romania at Isaccea in search of refuge.

In the 16th century, the town was located on the Moldavian-Ottoman border and its bazaar was one of the four most important trading posts in the Dobruja, with tradesmen coming from distant places, such as Chios or Ragusa.

[68] Industry is based on extraction of rock from a nearby quarry and woodworking, a tobacco processing factory and a winery.