Karamles is a very old town and is believed to be among the first human colonies, hence, it was visited by almost all Mesopotamian archeologists who were searching for the ruins of old Assyria and Babylonia. The first who started those archeological works in the hills of Karamles was the famous Englishman Austin Henry Layard in 1846 who noted that "..based on the Assyrian remains discovered in Karamles, it's believed that this Assyrian city was as great during its time as that of Khorsabad.." Many relief sculptures which contained cuneiform scripts were found in Tel Ghanim and Tel Barbara (two of the hill surrounding Karamles). In them were found the names of Assyrian Kings of Sargon and Shalmensar. Also, was found in Tel Barbara the remains of an Assyrian temple while at Tel Ghanim was found the remains of an Assyrian palace.

Karamles lost its important stature during the era of Shalmensser III (858-824 BC) whose son Assur-Daneen-Ablo led a rebellion against his father along with another 27 cities. His father empowered his other brother Shamshi-Adad, the Governor of Kaleh (Namrod). This civil war lasted for four years 827-824 BC with the destruction of the rebellion, however, Karamles being close to Kaleh did not survive the ravages of the war. Karamles was so impacted by that rebellion that its people left it and was given the name of "Oro-Karmash" meaning "The Ruined City". Actually, and till today Karamles is referred to by its Assyrian neighbors as "Karmash". However, Karamles was reinvograted during the reigns of Kings Shalmensser V (726-722 BC) and Sargon II (721-705 BC) who used it as his temporary capital.

The Battle of Karamles 331 BC
This great historical battle between the Greek Alexander of Macedonia and the Persian Emperor Daryos Dara III which ended with the defeat of the latter and the ushering of the Greek reign over the Near East. Karamles at the time was called Ko-Komle (which meant in Aramaic "The Camels' Square") after the death of most of the Camels of the Persian Emperor Daryos Dara I around the city due to their exhaustion. Hence, historically the Battle of Karamles is known as the Battle of Ko-Komle.

Karamles as Center for the Patriarchy of The Church of the East In 1332 Mar Denkha II decided to move the Seat of the Church of the East to Karamles away from Baghdad, Erbil, and Maraga due to the peacful and stable rule of its governors. The Seat of the Patriarchy in Karamles lasted 94 years. It was occupied by Patriarch Denkha II (1332-1380), Patriarch Eleya IV ; (1380-1408), and Shamoun II (1418-1427) who moved the Seat to Alqosh in 1426.

The oldest Christian building in Karamles is Mar Gewargis Church which was built during the sixth century. Also, was built around the beginning of the seveth century Mar Yonan Monastery.

As to the Mart (Saint) Maryam Daughters' Monastery, which was built next to Mar (Saint) Gewargis Church, this Monastery suffered tremendously at the hands of Mongol in the 13th century and in the 18th century at the hands of Ismail Pasha of Rawandows. Also, in Karamles is the Church of the Forty Martyrs (Beth Sahda) built in the 13th century.

The current fame of Karamles is due to its Church of St. Barbara which was built on the ruins of an Assyrian temple for the God Bano. Barbara is the daughter of the pagan Governor of Karamles in the first century who professed her Christianity followed by her servant Yolena which forced the Governor to imprison both of them. His pleas with his daughter to repent went unheeded which forced him to satisfy the priests of the Zoroastian temple and executed her in one of the rooms of that temple which became the grounds for the Church named after her and which still contain her remains and that of her servant. During the raid of Nader Shah in 1734 this church suffered tremendous damages, however, the people of Karamles rebuilt the church in 1798.

There are two more churches in Karamles, Church of the Virgin which was built in 1887 and Mar Addi Church, the newest of Karamles' churches which was completed in 1963.a

Karamles as Center of Principality
During the 13th and 14th centuries, Karamles became the center of a principality and gained fame due to that and was mentioned in several books as a trade center of immense importance. Among some of her governors are: 1. Prince Masoud (1317) 2. Prince Nasser El-Deen 3. Prince Hassan (1358) 4. Prince Matti (brother of Prince Hassan) 5. Prince Beyazeed (1364) 6. Prince Sahab Masoud (end of 14th century)

The Destruction of Nader Shah
During the never ending wars between the Persian and Ottoman Empires, Nader Shah of Persia decided in 1732 to attack and occupy Mesopotamia which was under the Ottoman rule. After occupying Baghdad the same year, he send a small part of his army (8,000 soldiers strong) to occupy Nineveh and its surroundings. However, his army was defeated which angered Nader Shah who decided in 1743 to go himself as a head of a 300,000 soldiers and 390 canons strong. After occupying Kirkuk and Erbil, he moved to Nineveh and its villages. To show his savage nature he decided to bomb Karamles before entering it. Most of the houses of the village were ruined, in addition to Mar Yohanan Church and Beth Sahda "Church of the Forty Martyrs". Nader Shah stayed four days in Karamles destroying and putting on fire everything he laid his hands on. The same was the fate of Bartella and Bakhdida. It was estimated that over 4,000 people were killed during those four days.