The region that forms today's Kayin State was part of successive Burmese kingdoms since the formation of the Pagan Empire in mid-11th century. During the 13th to 16th centuries, much of the region belonged to the Hanthawaddy Kingdom while the northern part of the region belonged to Taungoo, which was a vassal state of Ava Kingdom. The region then became part of Taungoo Dynasty and Konbaung Dynasty from 16th to 19th centuries. The British seized the southern third of today's Kayin State (below the Salween River) after the First Anglo-Burmese War (1824-1826), and the rest after the Second Anglo-Burmese War of 1852.
Towards the end of the British colonial era (1945-1948), the Karen leadership insisted on a separate state covering today's Kayin State and much of Mon State and Taninthayi Region, within the British Empire. They refused to sign the Panglong Agreement of February 1947, which was the basis for the 1947 Constitution of Burma, and boycotted the pre-independence elections of April 1947. Nonetheless, the constitution granted the Karen a state, though with an area less than what the Karen leadership had asked for from the British. The constitution also guaranteed states with the right to secede from the Union after a period of 10 years. (The Panglong Agreement gave only the Shan and the Kachin a state each; the Chin who actually signed the agreement did not receive a state.) The Karen National Union, which dominated the Karen leadership, was not satisfied, and wanted outright independence. In 1949, the KNU raised a rebellion that continues up to today. The KNU celebrates January 31 as 'revolution day', marking the day they went underground at the battle of Insein.
Much of the state has been a battlefield since then. The civilians have taken the brunt of the war. The KNU today forms the world's longest running resistance. The English name of the state was changed to Kayin State from Karen State in 1989 by the military government.