In the 15th century, after a long economical and political decline, Georgia became neighbors with the increasingly volatile and aggressive Ottoman Empire, and from the 16th century with the Safavid Empire. From the 16th century and for the next three centuries to come the kingdom was, with brief intermissions, under the suzerainty of the Persians.
Georgia experienced a high degree of civil instability, feudal separatism, and civil wars. The defeat of George VIII in the Battle of Chikhori against rebellious noble Bagrat, who proclaimed himself the King of Imereti, marked the beginning of the final disintegration of united Georgian monarchy and the state. In 1465, George VIII was captured by Kvarkvare II Jaqeli the Atabeg of Samtskhe (Meskheti). Sensing opportunity, Bagrat VI immediately proclaimed himself King of Kartli as well and took control of it in 1466. Kvarkvare, fearing that Bagrat would gain too much power, released George VIII from captivity, but the king was unable to reclaim the crown and only managed to proclaim himself King of Kakheti, creating even more fragmentation.
Bagrat VI continued to rule Kartli until 1478, when he was challenged by yet another pretender to the throne, Constantine II. Inter-feudal strife continued even during the reign of Constantine, who lost the Battle of Aradeti with Kvarkvare in 1483, with Alexander son of Bagrat VI proclaiming himself as the king of the all Western Georgia in 1484. The attempts of Constantine II, in 1489, to restore his rule over united kingdom of Kartli-Imereti were unsuccessful. In 1490, he was finally forced to recognize the splitting of Georgian kingdom into kingdoms of Kartli, Imereti, Kakheti and the Principality of Meskheti.
The new realms were not long at peace. Soon after coming into power, George II of Kakheti launched an expedition against Kartli, intending to depose King David X and conquer his kingdom. David's brother Bagrat successfully defended the kingdom and managed to capture George II in an ambush. Peace didn't linger in the west either, as David X faced incursions from Alexander II of Imereti, who was somewhat less successful than his Kakhetian counterpart. In 1513 the Kingdom of Kartli conquered Kakheti but only for a short time – the Kingdom of Kakheti was restored with the support of local nobles by Levan of Kakheti, son and heir of George II, in 1520.
The Peace of Amasya (1555) recognized Kartli, Kakheti and eastern Samtskhe as Persian possessions, while everything to the west of it (i.e. Imereti, western Samtskhe) fell in Ottoman hands. The next two centuries to come, Kartli was an integral part of the successive dynasties of Persia. It regularly paid tribute and sent gifts (pīškeš) to the shah in the form of boys and girls for use as slaves; horses; and wines. In 1747 the Shah of Persia, Nader Shah was assassinated. Capitalizing on the eruption of instability Teimuraz II and his son Erekle II, who had been given the kingship of Kartli and Kakheti respectively by Nader Shah himself as a reward for their loyalty, declared de facto independence. After Teimuraz II's death in 1762, Erekle II assumed control over Kartli, thus unifying the two into the short-lived Kingdom of Kartli-Kakheti. Following the Treaty of Georgievsk (1783) and Agha Mohammad Khan Qajar's brief re-occupation of eastern Georgia, the Kingdom of Kartl-Kakheti was annexed by the Russian Empire in 1801. Russian control over Kartli-Kakheti was finalized with Qajar Iran by the Treaty of Gulistan of 1813.